Facile green synthesis and potent antimicrobial efficacy of β-aminoheteronapthol via tailored Betti's protocol and their bis-aryl hydrazone click products

Article abstract of DOI:10.1007/s12039-013-0509-4

A series of novel Mannich base and their hydrazone derivatives were synthesized by highly resourceful, chic, simple and green technique with exceptionally facile reaction conditions of one-pot, three component reaction with an array of biologically and ph

Full text of DOI:10.1007/s12039-013-0509-4

c
J. Chem. Sci. Vol. 125, No. 6, November 2013, pp. 1573–1594. ꢀ Indian Academy of Sciences.
Facile green synthesis and potent antimicrobial efficacy
of β-aminoheteronapthol via tailored Betti’s protocol
and their bis-aryl hydrazone click products
K M KHANDARKARa,b,∗, M D SHANTIa, M AHMEDc and J S MESHRAMa
aDepartment of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440 033, India
bApplied Chemistry Department, G H Raisoni Academy of Engineering and Technology,
Nagpur 440 016, India
cDepartment of Chemistry, Government Polytechnic Sakoli, Bhandara 441 802, India
e-mail: kirankhandarkar@gmail.com
MS received 27 March 2013; revised 23 June 2013; accepted 4 July 2013
Abstract. A series of novel Mannich base and their hydrazone derivatives were synthesized by highly
resourceful, chic, simple and green technique with exceptionally facile reaction conditions of one-pot, three
component reaction with an array of biologically and pharmaceutically active novel heterocycles. The proto-
col offers a valuable alternative to known methods and will find applications in the field of green synthesis
and antimicrobial study against pathogenic microbes, supporting the development of bioinformatical database
of novel and derelict heterocycles. These data indicate their potential to become antifungal agents. The novel
products were established by elemental, IR, mass spectroscopic and NMR analysis. The environmental advan-
tages of the method include short reaction time, excellent yield, easy work-up, absence of extraction and
chromatographic purification steps.
Keywords. Green synthesis; zeolite catalyst; click reaction; antimicrobial efficacy.
1. Introduction
scientific community. Hence the usage of most of the
existing antimicrobials have limited capacity in over-
coming the threat of resistance and it is limited not
only by the rapidly developing drug resistance, but also
the unsatisfactory status of present treatments of bacte-
rial and fungal infections and drug side effects.2 Thus
it would be advantageous to provide a pharmacophore
species with useful properties that can be used commer-
cially against pathogenic and resistant microbes.
Mannich bases had abundant commercial appli-
cations and it was estimated that at least 35% of
Mannich bases related articles are published in phar-
maceutical journals. The first synthesis of racemic
Mannich-bases of 2-naphthol was achieved by Betti at
the turn of the twentieth century.3 Thereafter numer-
ous modifications of this reaction surfaced.4 Since these
compounds have multiple centres for chelation with
metal ions, they are likely to be potent inhibitors of
metallo-enzymes.5 Also, these compounds have the
potential to be used as scavengers in cases of heavy
metal poisoning.6 They have a broad range of biologi-
cal activities including diuretic, anticonvulsant, antipsy-
chotic, antimalarial, antiviral, centrally acting muscle
relaxant, and anticancer. Also, Mannich-bases of
various bioactive compounds have been prepared as
The incidence of microbial infections in the immune
compromised population has significantly increased
over the past several years. In particular, Candida species,
especially Candida albicans, are often significant
pathogens in patients infected with human immunode-
ficiency virus (HIV). Another pathogen, Pneumocysist
carinii, causes a form of pneumonia (PCP) that is
believed to be one of the leading causes of death in
patients suffering from AIDS. Furthermore, the treat-
ment of infectious diseases is more complicated in
immuno-suppressed patients, such as those infected
with the HIV, undergoing anticancer treatment and
organ transplants. Therefore, there is a vital need for
the development of new antimicrobial agents having
potent activity against the resistant microorganisms.1
The rapid development of resistance to existing
antibacterial and antifungal drugs posses a major threat
to public health which creates a serious challenge to the
∗For correspondence
1573

1574
K M Khandarkar et al.
prodrugs as means of overcoming some of their limi- click reactions are well-known, and their applications
tations.7 So keeping importance of Mannich-base moi- have revolutionized numerous fields including bio-
ety in mind, we had synthesized a series of substituted conjugate chemistry, material chemistry and polymer
coumarin derivatives via classical Betti’s condensa- sciences.22–25 The non-aldol addition reaction between
tion reaction with their pharmacophores modelling and a carbonyl and a nucleophilic nitrogen as a click
in vitro microbial activity.8 Despite the importance of reaction has key benefits of availability of amines for
the compounds, the serious downsides of their com- bioconjugation, rapid incorporation into molecular
mercial syntheses include some or all of the following: frameworks, and a simple resultant click product that
refluxing for extensive reaction time, large quantities of minimally impacts the nature of the biomolecules.26
mineral or Lewis/Bronsted acids as activators, which
Against this background, and also in the context of
on work-up are hydrolysed with generation of large our interest in the synthesis of biologically significant
quantities of corrosive and toxic waste by-products; the heterocycles via multi-component and click reactions,
use of stoichiometric quantities of reagents that produce we report here the green preparation of a library of phar-
metal salts as waste; poor yields; or production of mix- macologically relevant click fused bisarylhydrazones,
tures of regioisomers with low selectivity. The enan- containing a Betti’s base fabricated by a process that
tioselective transformations and industrial applications combines the use of zeolite with the synthetic effi-
are the foremost impediment in the microwave-assisted ciency associated with MCRs, providing a convergence
synthesis of these compounds.
of reaction and environmental economies.27
The aforementioned problems of greener synthetic
In this paper, green synthesis of potent Betti’s prod-
approach of Betti’s reaction product are overcome in uct and hydrazone derivatives are exemplified with
present work by one-pot multicomponent zeolite cata- their antimicrobial efficacy. Here, in order to reduce
lysed condensation bioactive Betti’s reaction products. the time period of Betti’s reaction product, enantio-
Inspired by the above facts and in continuation of our selective transformations and to achieve green chemi-
ongoing research programme in the field of synthe- cal synthesis, the reaction was carried out in catalytic
sis and antimicrobial activity of medicinally impor- medium of zeolites which enhance reaction rate, sup-
tant compounds,9 we report here the click synthesis of port reagents, regioselectivity, entrain by-products and
novel hydrazide-hydrazone/bisaryl hydrazone deriva- enhance product selectivity.28–30
tives of bioactive Betti’s product and evaluated them for
antimicrobial activity.
Furthermore, we have found a novel series of Betti’s
products and hydrazone derivatives that are effec-
Hydrazones are the most important pharmacophoric tive against resistant microbes, and provide significant
cores of several antimicrobial, anticonvulsant, anal- activity advantage over the art. It has been found that the
gesic, antiinflammatory, antinociceptive, antiplatelet, compounds of this innovation and composition contain-
antitubercular, and antitumoural drugs.10 Hydrazides ing these compounds are effective antimicrobial agents
and hydrazones are present in many of the bioac- against a broad range of pathogenic microorganisms
tive heterocyclic compounds that are of wide interest with advantages in low susceptibility to microbial resis-
because of their diverse biological and clinical applica- tance, reduced toxicity, and improved pharmacology.
tions. This created interest in researchers who have syn-
thesized variety of hydrazide derivatives and screened
them for their various biological activities.11 Hydra-
zones have been explored for the reversible conjuga-
2. Experimental
tion12 and labelling13 of biomolecules. However, their The solvents and reagents used in the synthetic work
application has been limited, as most hydrazones are were of analytical grade obtained from Qualigens India
prone to hydrolysis and premature cleavage, whereas and were purified by distillation where necessary. Melt-
hydrazones (and oximes) that are fully stable under
biological and mildly acidic conditions undergo slower
hydrolysis and are difficult to exchange or cleave.
The formation kinetics of the bis-aryl hydrazone
bond are 20 to 900 times higher than those of conven-
tional hydrazone/oxime bonds between alkyl aldehydes/
ketones and alkyl hydrazide or aminoxy probes.14
The hydrazide hydrazones have been demonstrated to
possess antibacterial,15–17 anticonvulsant18–20 and anti-
tubercular21 activities. Furthermore, the benefits of
ing points were determined in open capillaries and
uncorrected. Infrared spectra were recorded on Bruker
Alfa-T with direct sampling for analysis. H NMR
spectra were recorded on a Cryo-magnet NMR Spec-
trometer 400 MHz (Bruker) instrument using tetra-
methylsilane (TMS) as an internal standard with CDCl3
and DMSO as a solvent. Chemical shifts are given
in parts per million (δ scale) and the coupling con-
stants are given in Hz. Mass spectra were recorded
on a Waters Micromass Q-T of Micro spectrometer.
1

Tailored Betti’s product and their click hydrazones
1575
The reactions were monitored and the purity of pro- lization) or 96% (3.978 g, filtration), m. p. 192–
ducts were checked out on Silica gel 60 F254 (Merck) 196◦C; refractive index nD22: 1.700. Anal. Calcd. for
TLC plates with a mixture of petroleum ether (60– C25H22N2O4: C, 72.45; H, 5.35; N, 6.76%. Found: C,
80◦C) and ethyl acetate as the eluent and the spots were 72.51; H, 5.39; N, 6.70%. IR (cm−1) υ: 3553.8 (OH),
visualized under ultraviolet light and iodine chamber. 1323.9 (C-N stretching), 3380.8(NH), 2852.2 (OCH3),
1
Elemental analyses were performed on a Perkin-Elmer 1722.5 (CO). H NMR (CDCl3, 400 MHz, ppm, J
2400 Series II elemental CHNS analyzer. The zeolitic Hz) δH : 9.92 (s, 1H, quinoline-OH); 7.64–8.18 (m,
raw mineral was ground and purified via washing with 5H, quinoline-H); 7.67 (s, 1H sec. amine HN-); 6.86–
distilled water by means of a fluidized bed process in 7.37 (m, 4H, Ar-H); 2.85 (s, 3H, -CH3); 5.919 (s, 1H,
order to remove the non-zeolitic mineral phases. After methine); 6.97–7.38 (m, 3H, vanillin -H); 3.08 (s, 3H,
vacuum filtration and drying at 200◦C, zeolites were vanillin -OCH3); 10.28 (s, 1H, vanillin -OH).13C NMR
reutilized for each reaction.
(CDCl3, 75 MHz, ppm) δC : 24.8, 57.1, 57.2, 112.0,
114.1, 116.8, 120.2, 120.8, 121.7, 122.2, 127.6, 128.4,
129.4, 129.7, 135.5,136.3, 137.3, 146.2, 148.2, 148.4,
148.7, 150.3, 152.0, 197.4. MS, m/z: 414 (M+, 100%).
2.1 General procedure for the synthesis
of β-amino-quinoline (5)
2.1c Ethyl 4-{[(2-hydroxyphenyl)(8-hydroxyquinolin-
7-yl)methyl]amino}benzoate (5c): Orange needle
shape solid, yield 97% (4.02 g, crystallization) or 99%
(4.1 g, filtration), m. p. 96–98◦C; refractive index nD22:
1.701. Anal. Calcd. for C25H22N2O4: C, 72.45; H, 5.35;
N, 6.76%. Found: C, 72.50; H, 5.38; N, 6.72%. IR
(cm−1) υ: 3582.4 (OH), 1734.9 (COOC2H5), 1305.5
(C-N stretching), 3431.6 (NH). 1H NMR (CDCl3,
400 MHz, δ ppm, J Hz): 10.13 (s, 1H, quinoline -OH);
7.47–8.13 (m, 5H, quinoline-H); 6.99 (s, 1H sec. amine
-NH); 6.79–7.98 (m, 4H, Ar-H) 1.31 (t, 3H, -CH3, J =
7.2); 4.23 (q, 2H, -OCH2-, J = 1.6, 4.2); 5.62 (s, 1H,
methine); 9.63 (s, 1H, -OH); 6.81–7.07 (m, 4H, Ar-H).
13C NMR (CDCl3, 75 MHz, ppm) δC : 15.6, 51.8, 61.3,
112.0, 116.4, 118.5, 119.5, 120.2, 120.9, 121.3, 121.8,
127.6, 128.4, 130.8, 132.3, 135.5, 137.3, 148.5, 151.0,
152.4, 158.6, 166.9. MS, m/z: 414 (M+, 100%).
A mixture of 8-hydroxyquinoline (3) (1 mmol) and car-
bonyl compound (1) (1 mmol) was stirred at room tem-
perature for 10 min in the presence of zeolite (0.5 g)
in ethanol. Then, an equimolar amount of primary or
secondary aromatic/aliphatic amine (2) was added, and
resulting reaction mixture was stirred for 1–1.5 h at
40◦C. After completion of the reaction (TLC checked),
the coloured solid that separated was filtered, washed
with ethanol and purified by recrystallization from
ethanol or by filtration through a pad of silica gel
using 9:1 petroleum ether–ethyl acetate to afford pure
compounds 5 (compounds 5a–5j).
2.1a Ethyl 4-{[(2-hydroxy-3-methoxyphenyl)(8-hydroxy-
quinolin-7-yl)methyl]amino}benzoate (5a): Light
yellow crystalline solid; yield 96% (4.267 g, crystalliza-
tion) or 99% (4.4 g, filtration), m.p. 173–175◦C; refrac-
tive index nD22: 1.681. Anal. Calcd. for C26H24N2O5: C,
70.26; H, 5.44; N 6.30%. Found: C, 70.35; H, 5.48; N,
6.28%. IR (cm−1) υ: 3088.4 (OH), 1707.2 (COOC2H5),
1324.3 (C-N stretching), 3382.6 (NH), 2872.3 (OCH3).
1H NMR (DMSO, 400 MHz, δH ppm, J Hz): 8.64 (s,
1H, quinoline -OH); 7.83–7.89 (m, 5H, quinoline-H);
7.98 (s, 1H, sec. amine -NH); 7.41–7.47 (m, 4H, Ar-
H) 1.32 (t, 3H, -CH3, J = 3.42); 3.91 (q, 2H, -OCH2-,
J = 1.68, 1.72); 7.49 (s, 1H, methine); 7.53–7.57 (m,
3H, vanillin-H); 8.06 (s, 1H, vanillin-OH); 2.55 (s, 3H,
vanillin –OCH3).13C NMR (CDCl3, 75 MHz, ppm) δC :
15.4, 44.2, 59.1, 64.6, 113.2, 113.5, 119.6, 121.2, 121.6,
122.2, 122.3, 123.0, 123.9, 127.5, 128.4, 130.7, 134.5,
137.6, 145.6, 149.2, 150.1, 151.9, 165.9. MS, m/z: 444
(M+, 100%).
2.1d Ethyl 4-{[(2-chloroquinolin-3-yl)(8-hydroxy-
quinolin-7-yl)methyl]amino}benzoate (5d): Dark yel-
low amorphous solid, yield 92% (4.452 g, crystal-
lization) or 95% (4.597 g, filtration), m.p. 225–229◦C;
refractive index nD22: 1.722. Anal. Calcd. for C28H22
N3O3Cl: C, 69.49; H, 4.58; N, 8.68; Cl, 7.33%. Found:
C, 69.53, H, 4.65; Cl, 7.35; N, 8.57%. IR (cm−1) υ:
3096.1 (OH), 1716.9 (COOC2H5), 1323.3 (C-N stretch-
1
ing), 3420.5 (N-H), 1066.8 (C-Cl). H NMR (DMSO,
400 MHz, δ ppm, J Hz): 9.11 (s, 1H, quinoline -OH);
7.45–8.69 (m, 5H, quinoline-H); 7.61 (s, 1H sec. amine
-NH); 6.79–7.97 (m, 4H, Ar-H) 1.32 (t, 3H, -CH3,
J = 7.2); 4.24 (q, 2H, -OCH2-, J = 7.0, 7.12); 6.43
(s, 1H, methine); 7.70–8.45 (m, 5H, chloroquinolin-
H).13C NMR (CDCl3, 75 MHz, ppm) δC : 15.5, 43.8,
60.9, 113.4, 118.6, 121.2, 121.6, 122.3, 126.5, 127.0,
2.1b 1-(4-{[(4-Hydroxy-3-methoxyphenyl)(8-hydroxy- 127.4, 127.5, 128.4, 129.9, 130.7, 130.9, 135.6, 136.2,
quinolin-7-l)methyl]amino}phenyl)ethan-1-one (5b): 137.8, 145.6, 148.6, 150.1, 151.9, 152.2, 166.3. MS,
Yellow amorphous solid, yield 93% (3.854 g, crystal- m/z: 483 (M+, 100%).

1576
K M Khandarkar et al.
2.1e 7-{[(1,5-Dimethyl-3-methylidene-2-phenyl-2,3-
120.9, 121.3, 124.4, 127.6, 128.4, 129.1, 130.7, 135.5,
137.3, 145.4, 148.5, 149.1, 150.9, 152.6, 166.3. MS,
dihydro-1H-pyrazol-4-yl)amino](furan-2-yl)methyl}
quinolin-8-ol (5e): Dark brown amorphous solid, m/z: 477 (M+, 100%).
yield 95% (4.051 g, crystallization) or 97% (4.136 g,
filtration), m.p. 166–170◦C; refractive index nD22:
2.1h Ethyl 4-{[1-(8-hydroxyquinolin-7-yl)-2-oxo-1,2-
1.734. Anal. Calcd. for C25H22N4O3: C, 70.41; H, 5.20;
N, 13.14%. Found: C, 70.29; H, 5.26; N, 13.20%.
IR (cm−1) υ: 3523.6.1 (OH), 1343.2 (C-N stretch-
diphenylethyl]amino}benzoate (5h): Yellow amor-
phous solid, yield 91% (4.573 g, crystallization) or 94%
(4.724 g, filtration), m.p. 112–116◦C; refractive index
nD22: 1.685. Anal. Calcd. for C32H26N2O4: C, 76.48; H,
5.21; N, 5.57%. Found: C, 76.55; H, 5.29; N, 5.51%.
IR (cm−1) υ: 3518.4 (OH), 1336.5 (C-N stretching),
1
ing), 3423.8 (N–H), 1743.8 (CO). H NMR (CDCl3,
400 MHz, δ ppm, J Hz): 9.71 (s, 1H, quinoline -OH);
7.45–8.68 (m, 5H, quinoline-H); 7.59 (s, 1H sec. amine
-NH); 6.79–7.42 (m, 5H, Ar-H); 2.32 (s, 3H, -CH3);
3.21 (s, 3H, N-CH3); 5.74 (s, 1H, methine); 7.28–7.32
(m, 3H, furan-H).13C NMR (CDCl3, 75 MHz, ppm)
δC : 14.2, 34.8, 54.6, 106.7, 110.8, 116.4, 120.1, 120.8,
121.4, 122.8, 123.9, 127.6, 128.4, 129.3, 131.5, 133.9,
135.5, 137.4, 142.1, 148.5, 150.5, 152.5, 160.7. MS,
m/z: 426 (M+, 100%).
1
3424.3 (NH), 1722.3 (COOC2H5), 1708.6 (CO). H
NMR (CDCl3, 400 MHz, δ ppm, J Hz): 9.87 (s, 1H,
quinoline -OH); 7.41–7.58 (m, 5H, quinoline-H); 7. 12
(s, 1H sec. amine -NH); 6.71–7.68 (m, 4H, Ar-H); 1.12
(t, 3H, -CH3, J = 7.0); 3.95 (q, 2H, -OCH2-, J =
4.0, 8.0); 7.23–7.92 (m, 10H, Ar-H). 13C NMR (CDCl3,
75 MHz, ppm) δC : 15.3, 61.4, 74.8, 112.0, 118.5, 120.0,
120.7, 121.3, 126.2, 127.6, 128.2, 128.4, 128.6, 128.8,
129.2, 130.7, 133.1, 136.0, 136.7, 137.3, 139.8, 148.5,
150.2, 152.3, 166.9, 196.5. MS, m/z: 502 (M+, 100%).
2.1f Ethyl 4-{[furan-2-yl(8-hydroxyquinolin-7-yl)
methyl]amino}benzoate (5f): Light brown amor-
phous solid, yield 98% (3.8 g, crystallization) or 99%
(3.845 g, filtration), m.p. 148–150◦C; refractive index
nD22: 1.674. Anal. Calcd. for C23H20N2O4: C, 71.12; H,
5.19; N, 7.21%. Found: C, 71.23; H, 4.98; N, 7.28%.
IR (cm−1) υ: 3356.4 (OH), 1323.3 (C-N stretching),
3113.5 (N–H), 1718.8 (COOC2H5), 1232.7 (COC). 1H
NMR (CDCl3, 400 MHz, ppm, J Hz) δH : 8.23 (s, 1H,
quinoline-OH); 7.36–7.44 (m, 5H, quinoline-H); 7.40
(s, 1H sec. amine HN-); 7.34–7.41 (m, 4H, Ar-H); 1.25
(t, 3H, -CH3, J = 5.6); 4.15 (q, 2H, -OCH2, J = 3.7,
4.6); 7.25 (s, 1H, methine); 7.32–7.37 (m, 3H, furan-
H). 13C NMR (CDCl3, 75 MHz, ppm) δC : 15.0, 54.6,
60.9, 106.8, 110.6, 113.7, 118.6, 120.2, 120.9, 121.8,
127.5, 128.7, 130.7, 135.4, 137.6, 142.4, 148.6, 150.3,
151.9, 152.5, 167.1. MS, m/z: 388 (M+, 100%).
2.1i 7-[1-(Tert-butylamino)-2-hydroxy-1,2-diphenyl-
ethyl]quinolin-8-ol (5i): Bright yellow crystalline
solid, yield 93% (3.836 g, crystallization) or 98%
(4.042 g, filtration), m.p. 102–105◦C; refractive index
nD22: 1.647. Anal. Calcd. for C27H28N2O2: C, 78.61; H,
6.84; N, 6.79%. Found: C, 78.72; H, 6.88; N, 6.72%.
IR (cm−1) υ: 3518.4 (aliphatic-OH), 3622.3 (aromatic-
OH), 1210.6 (C-N stretching), 3321.7(NH), 1361.4
1
(tert-butyl). H NMR (CDCl3, 400 MHz, δ ppm, J
Hz): 10.02 (s, 1H, quinoline -OH); 7.39–7.61 (m, 5H,
quinoline-H); 7.68 (s, 1H sec. amine -NH); 1.32 (s, 9H,
-CH3); 6.43 (s, 1H, methine); 5.27 (s, 1H, -OH); 7.26–
7.43 (m, 10H, Ar-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 30.3, 48.7, 60.8, 90.2, 120.2, 120.9, 121.3, 126.2,
127.1, 127.6, 128.2, 128.4, 128.9, 129.2, 135.5, 137.3,
140.6, 141.2, 148.5, 150.0. MS, m/z: 412 (M+, 100%).
2.1g Ethyl 4-{[chloro(8-hydroxyquinolin-7-yl)(4-nitro-
phenyl)methyl]amino}benzoate (5g): Light orange
crystaline solid, yield 97% (4.635 g, crystallization) or 2.1j 7-{[(6-Benzyl-6H-purin-6-yl)amino](4-hydroxy-
99% (4.732 g, filtration), m.p. 182–186◦C; refractive 3-methoxyphenyl)methyl}quinolin-8-ol (5j): Orange
index nD22: 1.697. Anal. Calcd. for C25H20ClN3O5: C, amorphous solid, yield 94% (4.742 g, crystallization)
62.83; H, 4.22; Cl, 7.42; N, 8.79%. Found: C, 62.88; or 97% (4.894 g, filtration), m.p. 116–120◦C; refractive
H, 4.30; Cl, 7.46; N, 8.72%. IR (cm−1) υ: 3466.7 index nD22: 1.719. Anal. Calcd. for C29H24N6O3: C,
(OH), 1346.3 (C-N stretching), 3213.4 (N-H), 1720.3 69.04; H, 4.79; N, 16.66%. Found: C, 69.12; H, 4.86;
(COOC2H5), 753.2 (C-Cl), 1465.3 (NO2). H NMR N, 16.60%. IR (cm−1) υ: 3122.3 (OH), 1326.7 (C-N
1
(CDCl3, 400 MHz, δ ppm, J Hz): 9.69 (s, 1H, quinoline stretching), 2847.9 (OCH3), (NH), 1845.2 (purine). 1H
-OH); 7.42–7.58 (m, 5H, quinoline-H); 7.61 (s, 1H sec. NMR (CDCl3, 400 MHz, δ ppm, J Hz): 9.57 (s, 2H,
amine -NH); 6. 19–6.56 (m, 4H, Ar-H); 1.62 (t, 3H, -OH); 7.43–7.65 (m, 5H, quinoline-H); 6.13 (s, 1H
-CH3, J = 6.1, 7.2); 4.34 (q, 2H, -OCH2-, J = 1.5, sec. amine -NH); 7.89 (s, 2H, purine-H); 2.67 (s, 2H,
1.6); 7.96–8.12 (m, 4H, Ar-H). 13C NMR (CDCl3, CH2); 7.12–7.24 (m, 5H, Ar-H); 5.39 (s, 1H, methine);
75 MHz, ppm) δC : 15.3, 61.5, 81.3, 112.2, 118.5, 120.2, 6.74–6.82 (m, 3H, Ar-H); 3.38 (s, 3H, -OCH3). 13C

Tailored Betti’s product and their click hydrazones
1577
NMR (CDCl3, 75 MHz, ppm) δC : 41.8, 44.21, 56.2, coumarin); 6.23–7.48 (m, 3H, coumarin-H); 2.10 (s,
65.6, 113.7, 117.4, 120.2, 120.9, 121.5, 122.3, 126.0, 3H, methyl-H); 6.33–7.81 (m, 3H, pyrrol-H); 6.49 (s,
127.5, 127.8, 128.5, 128.8, 135.9, 136.4, 137.6, 139.5, 1H, methine); 6.08–7.58 (m, 3H, furan-H). 13C NMR
143.2, 148.6, 150.2, 151.9, 154.6, 163.6, 166.8. MS, (CDCl3, 75 MHz, ppm) δC : 18.9, 28.0, 47.5, 106.7,
m/z: 504 (M+, 95%).
110.6, 111.0, 112.0, 112.5, 117.7, 119.6, 123.2, 126.7,
129.9, 142.1, 151.8, 152.5, 152.7, 155.7, 160.8, 188.9.
MS, m/z: 363 (M+, 100%).
2.2 General procedure for the synthesis
of β-amino-chromene (6)
2.2c 8-[(2-Acetyl-1H-pyrrol-1-yl)(4-methoxyphenyl)
methyl]-7-hydroxy-4-methyl-2H-chromen-2-one (6c):
Dull yellow amorphous solid, yield 90% (3.63 g,
crystallization) or 97% (3.913 g, filtration), m.p. 130–
134◦C; refractive index nD22: 1.620. Anal. Calcd. for
C24H21NO5: C, 71.45; H, 5.25; N, 3.47%. Found: C,
71.58; H, 5.34; N, 3.41%. IR (cm−1) υ: 3526.9 (OH),
1647.1 (cyclic CO), 1353.6 (C-N stretching), 2837.4
A mixture of coumarin (4) (1 mmol) and carbonyl
compound (1) (1 mmol) in ethanol was stirred at
40◦C for 15 min in the presence of zeolite (0.5 g).
Then, an equimolar amount of primary or secondary
aromatic/aliphatic amine (2) was added, and result-
ing reaction mixture was stirred for 1–2 h. After com-
pletion of the reaction (TLC checked), the coloured
solid that separated was filtered, washed with ethanol
and purified by recrystallization from ethanol/methanol
or by filtration through a pad of silica gel using 9:1
petroleum ether–ethyl acetate to afford pure compounds
6 (compounds 6a–6g).
1
(OCH3), 1719.9 (CO). H NMR (CDCl3, 400 MHz,
ppm, J Hz) δH : 10.18 (s, 1H, coumarin-OH); 2.34 (s,
3H, methyl coumarin); 6.21–7.46 (m, 3H, coumarin-
H); 1.94 (s, 3H, methyl-H); 6.42–7.68 (m, 3H, pyrrol-
H); 7.26 (s, 1H, methine); 3.92 (s, 3H, methoxy-H);
6.69–7.14 (m, 4H, Ar-H). 13C NMR (CDCl3, 75 MHz,
ppm) δC : 18.2, 29.2, 54.8, 55.8, 111.1, 112.4, 112.8,
113.3, 115.0, 120.6, 123.2, 123.8, 126.5, 129.1, 129.8,
130.1, 151.2, 152.7, 154.9, 158.1, 161.3, 189.4. MS,
m/z: 403 (M+, 100%).
2.2a 4-{[(4-Hydroxy-3,5-dimethoxyphenyl)(7-hydroxy-
4-methyl-2-oxo-2H-chromen-8-yl)methyl]amino}benzoic
acid (6a): Orange needle-shaped solid, yield 95%
(4.535 g, crystallization) or 97% (4.631 g, filtration),
m.p. 89–94◦C; refractive index nD22: 1.679. Anal.
Calcd. for C26H23NO8: C, 65.40; H, 4.86; N, 2.93%.
Found: C, 65.55; H, 5.01; N, 2.82%. IR (cm−1) υ:
3627.3 (OH), 1595.2 (CO), 1345.8 (C-N stretching),
2.2d Ethyl 4-{[(2-chloroquinolin-3-yl)(7-hydroxy-4-
methyl-2-oxo-2H-chromen-8-yl)methyl]amino}benzoate
(6d): Bright yellow amorphous solid, yield 96%
(4.943 g, crystallization) or 97% (5.0 g, filtration), m.p.
98–101◦C; refractive index nD22: 1.691. Anal. Calcd.
for C29H23ClN2O5: C, 67.64; H, 4.50; Cl, 6.88; N,
5.44%. Found: C, 67.72; H, 4.58; Cl, 6.92; N, 5.38%.
IR (cm−1) υ: 3498.3 (OH), 1715.6 (cyclic CO), 3419.9
(NH), 1277.7 (C-N stretching), 1732.4 (COOC2 H5),
1
3413.7 (NH), 1396.3 (COOH), 2815.9 (OCH3). H
NMR (CDCl3, 400 MHz, ppm, J Hz) δH : 10.62 (s, 1H,
coumarin-OH); 2.38 (s, 3H, methyl coumarin); 6.23–
7.48 (m, 3H, coumarin-H); 6.81 (s, 1H, sec. amine
-NH) 13.74 (s, 1H, COO-H); 6.78–7.84 (m, 4H, Ar-H);
5.16 (s, 1H, methine); 6.40 (s, 2H, Ar-H); 3.83 (s, 6H, -
OCH3); 8.73 (s, 1H, -OH). 13C NMR (CDCl3, 75 MHz,
ppm) δC : 19.4, 51.2, 56.1, 106.0, 112.0, 112.5, 112.7,
113.1, 118.6, 123.0, 123.7, 131.1, 134.9, 137.3, 147.9,
151.0, 152.7, 152.8, 154.9, 161.3, 170.1. MS, m/z: 477
(M+, 100%).
1
1098.6 (Cl). H NMR (DMSO, 400 MHz, ppm, J Hz)
δH : 10.53 (s, 1H, coumarin-OH); 2.37 (s, 3H, methyl
coumarin); 6.55–7.46 (m, 3H, coumarin-H); 6.80 (s,
1H, sec. amine -NH); 6.71–7.61(m, 4H, Ar-H); 1.33 (t,
3H, -CH3, J = 8.0); 4.32 (q, 2H, -CH2, J = 4.0, 8.0);
6.14 (s, 1H, methine); 7.74–9.22 (m, 5H, quinoline-H).
13C NMR (CDCl3,75 MHz, ppm) δC : 13.8, 20.1, 45.8,
61.2, 112.0, 112.2, 112.5, 112.7, 118.6, 122.6, 124.4,
126.7, 127.0, 127.5, 130.1, 130.7, 131.0, 136.2, 142.4,
147.4, 150.2, 152.4, 153.6, 155.1, 161.6, 166.7. MS,
m/z: 514 (M+, 100%).
2.2b 8-[(2-Acetyl-1H-pyrrol-1-yl)(furan-2-yl)methyl]-
7-hydroxy-4-methyl-2H-chromen-2-one (6b): Light
brown amorphous solid, yield 87% (3.161 g, crystal-
lization) or 97% (3.524 g, filtration), m.p. 166–170◦C;
refractive index nD22: 1.645. Anal. Calcd. for
C21H17NO5: C, 69.41; H, 4.72; N, 3.85%. Found:
C, 69.52; H, 4.78; N, 3.83%. IR (cm−1) υ: 3410.5 2.2e Ethyl 4-{[(7-hydroxy-4-methyl-2-oxo-2H-chromen-
(OH), 1645.2 (cyclic CO), 1352.7 (C-N stretching), 8-yl)(4-oxo-4H-chromen-2-yl)methyl]amino}benzoate
1720.5 (CO). 1H NMR (CDCl3, 400 MHz, ppm, J Hz) (6e): Pale green crystalline solid, yield 90% (4.477 g,
δH : 9.68 (s, 1H, coumarin-OH); 2.42 (s, 3H, methyl crystallization) or 97% (4.825 g, filtration), m.p.

1578
K M Khandarkar et al.
140–142◦C; refractive index nD22: 1.679. Anal. Calcd. 2.3 General procedure for the synthesis
for C29H23NO7: C, 70.01; H, 4.66; N, 2.82%. Found: C, of Nꢁ-substituted arylidenehydrazine derivatives (7)
70.11; H, 4.73; N, 2.76%. IR (cm−1) υ: 3457.7 (OH),
β-aminoheteronapthol (5/6) (1 mmol) and aldehyde/
ketone (1 mmol) were made single phase by dissolving
in minimum quantity of ethanol and then added to petri
1714.6 (cyclic CO), 3436.3 (NH), 1358.3 (C-N stretch-
ing), 1735.7 (COOC2 H5). 1H NMR (DMSO, 400 MHz,
ppm, J Hz) δH : 11.81 (s, 1H, coumarin-OH); 1.33 (s,
dish containing hydrazine hydrate (80%) (1 mmol).
3H, methyl coumarin); 7.09–7.95 (m, 3H, coumarin-
This concoction was then mixed with a glass rod, a
H); 5.98 (s, 1H, methine); 3.82 (s, 1H sec. amine HN-);
dry solid product established within 10 s by exother-
mic click reaction at room temperature. The solid pro-
7.56–7.98 (m, 4H, Ar-H); 1.10 (t, 3H, -CH3, J = 8.0);
4.33 (q, 2H, -OCH2, J = 4.0, 8.0); 7.14–8.18 (m,
duct was washed with cold ethanol and recrystallized
5H, Chromon-H). 13C NMR (CDCl3, 75 MHz, ppm)
by ethanol 7 (compound 7a–7p).
δC : 14.6, 19.2, 53.6, 61.2, 110.1, 111.9, 112.1, 112.4,
112.6, 116.3, 118.6, 122.5, 123.4, 124.2, 124.6, 125.9,
2.3a Nꢁ-[(2-fluorophenyl)methylidene]-4-{[(2-hydroxy-
3-methoxyphenyl)(8-hydroxyquinolin-7-yl)methyl]amino}
130.8, 135.2, 149.8, 150.3, 152.6, 153.6, 157.4, 161.6,
166.3, 167.3, 178.2. MS, m/z: 497 (M+, 100%).
benzohydrazide (7a): Light yellow crystalline solid,
yield 90% (4.828 g, crystallization) or 95% (5.097 g,
filtration), m.p. 104–108◦C; refractive index nD22:
2.2f Ethyl 4-{[(7-hydroxy-4-methyl-2-oxo-2H-chromen-
1.649. Anal. Calcd. for C31H25FN4O4: C, 69.39; H,
4.70; F, 3.54; N, 10.44%. Found: C, 69.45; H, 4.79; F,
3.58; N, 10.38%. IR (cm−1) υ: 3089.1 (OH), 1675.2
(C=N-), 1321.9 (C-N stretching), 3382.8 (NH), 2852.0
8-yl)diphenylmethyl]amino}benzoate (6f): Dark Green
amorphous solid, yield 92% (4.651 g, crystallization)
or 97% (4.9 g, filtration), m.p. 105–109◦C; refractive
index nD22: 1.656. Anal. Calcd. for C32H27NO5: C,
76.02; H, 5.38; N, 2.77%. Found: C, 76.11; H, 5.46;
N, 2.69%. IR (cm−1) υ: 3467.3 (OH), 1712.9 (cyclic
CO), 3438.4 (NH), 1357.9 (C-N stretching), 1736.8
(COOC2 H5). 1H NMR (CDCl3, 400 MHz, ppm, J Hz)
δH : 10.96 (s, 1H, coumarin-OH); 2.12 (s, 3H, methyl
coumarin); 6.23–7.48 (m, 3H, coumarin-H); 5.72 (s, 1H
sec. amine HN-); 6.71–7.68 (m, 4H, Ar-H); 1.29 (t, 3H,
-CH3, J = 5.2); 4.30 (q, 2H, -OCH2, J = 3.8, 4.6);
7.23–7.43 (m, 10H, Ar-H). 13C NMR (CDCl3, 75 MHz,
ppm) δC : 13.9, 19.6, 59.5, 61.2, 112.1, 112.5, 112.7,
113.2, 118.5, 123.1, 123.8, 126.3, 127.2, 130.1, 130.8,
145.1, 151.2, 152.0, 152.7, 154.8, 161.1, 165.9. MS,
m/z: 505 (M+, 100%).
1
(OCH3), 1096.7 (CF). H NMR (CDCl3, 400 MHz,
δH ppm, J Hz): 8.68 (s, 2H, -OH); 7.74–7.82 (m, 5H,
quinoline-H); 8.12 (s, 1H, sec. amine -NH); 7.36–7.42
(m, 4H, Ar-H); 10.82 (s, 1H, HN-hydrazide); 8.93 (s,
1H, methylene); 7.47–7.63 (m, 4H, Ar-H); 7.55 (s, 1H,
methine); 7.31–7.43 (m, 3H, vanillin-H); 1.34 (s, 3H,
vanillin –OCH3). 13C NMR (CDCl3, 75 MHz, ppm) δC :
50.2, 56.3, 109.5, 112.4, 116.0, 118.3, 120.4, 120.6,
121.0, 121.4, 121.7, 122.9, 123.7, 124.4, 127.7, 128.4,
130.2, 130.8, 132.6, 135.6, 137.3, 143.4, 144.6, 148.5,
150.1, 159.7, 163.3. MS, m/z: 536 (M+, 100.0%).
2.3b 7-[(4-Hydroxy-3-methoxyphenyl)({4-[(1)-1-{2-[(4-
methoxyphenyl)methylidene]hydrazin-1-ylidene}ethyl]
phenyl}amino)methyl]quinolin-8-ol (7b): Dull orange
amorphous solid, yield 93% (5.083 g, crystallization)
or 97% (5.3 g, filtration), m.p. 106–110◦C; refractive
index nD22: 1.630. Anal. Calcd for C33H30N4O4: C,
72.51; H, 5.53; N, 10.25%. Found: C, 72.68; H, 5.70;
N, 10.21%. IR (cm−1) υ: 3551.9 (OH), 1324.2 (C-
N stretching), 3380.8(NH), 2849.1 (OCH3), 1726.5
2.2g 8-[Furan-2-yl(morpholin-4-yl)methyl]-7-hydroxy-
4-methyl-2H-chromen-2-one (6g): Light brown amor-
phous solid, yield 95% (3.242 g, crystallization) or
97% (3.311 g, filtration), m.p. 97–100◦C; refractive
index nD22: 1.612. Anal. Calcd. for C19H19NO5: C,
66.85; H, 5.61; N, 4.10%. Found: C, 66.93; H, 5.56;
N, 4.12%. IR (cm−1) υ: 3105.4 (OH), 1759.1 (cyclic
1
(C=N-). H NMR (CDCl3, 400 MHz, ppm, J Hz) δH :
1
CO), 1343.5 (C-N stretching), 1769.8 (morpholin). H
9.89 (s, 2H, -OH); 7. 62–8.17 (m, 5H, quinoline-H);
6.70 (s, 1H sec. amine HN-); 6.84–7.38 (m, 4H, Ar-H);
3.12 (s, 3H, -CH3); 8.88 (s, 1H, methylene); 7.16–7.74
(m, 4H, Ar-H); 3.03 (s, 3H, Ar-OCH3); 5.19 (s, 1H,
methine); 6.91–7.34 (m, 3H, vanilin-H); 10.23 (s, 3H,
vanilin-OH). 13C NMR (CDCl3, 75 MHz, ppm) δC :
14.6, 55.7, 56.0, 56.3, 112.1, 113.8, 114.6, 116.3,
120.2, 120.9, 121.4, 121.9, 127.0, 127.6, 128.1, 128.5,
130.0, 133.7, 135.5, 136.3, 137.3, 146.2, 148.0, 148.5,
NMR (CDCl3, 400 MHz, ppm, J Hz) δH : 10.26 (s,
1H, coumarin-OH); 2. 23(s, 3H, methyl caumain);
6.45–7.47 (m, 3H, coumarin-H); 3.59 (t, 4H, J = 4.2);
2.67 (t, 4H, J = 6.0); 6.15 (s, 1H, methine); 6.28–7.65
(m, 3H, furan-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 20.2, 48.4, 52.9, 67.4, 106.8, 110.6, 111.8, 112.7,
112.9, 116.4, 124.8, 142.4, 151.7, 152.6, 152.7, 155.5,
161.8. MS, m/z: 341 (M+, 100%).

Tailored Betti’s product and their click hydrazones
1579
149.4, 149.9, 150.1, 162.8, 197.3. MS, m/z: 546 (M+, (cm−1) υ: 3525.6 (OH), 1728.7 (C=N-), 1348.1 (C-N
100.0%).
stretching), 3430.8 (N–H). 1H NMR (CDCl3, 400 MHz,
δ ppm, J Hz): 9.70 (s, 1H, quinoline -OH); 7.42–8.66
(m, 5H, quinoline-H); 7.60 (s, 1H sec. amine -NH);
6.80–7.37 (m, 5H, Ar-H); 2.35 (s, 3H, -CH3); 3.11 (s,
3H, N-CH3); 8.54 (s, 1H, methylene); 13.34 (s, 1H,
vanillin-OH); 3.43 (s, 3H, vanillin-OCH3); 6.84–7.22
(m, 3H, vanillin-H); 5.18 (s, 1H, methine); 6.26–7.25
(m, 3H, furan-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 9.4, 34.2, 53.8, 56.1, 106.7, 109.2, 110.6, 115.0,
116.6, 119.6, 120.2, 120.9, 121.3, 122.8, 123.9, 124.4,
127.6, 128.4, 129.2, 135.5, 136.2, 126.0, 137.3, 142.1,
148.5, 149.1, 150.3, 150.6, 152.3, 157.3, 164.1. MS,
m/z: 574 (M+, 100%).
2.3c 4-{[(2-Hydroxyphenyl)(8-hydroxyquinolin-7-yl)
methyl]amino}-Nꢁ-(1-phenylethylidene) benzohydrazide
(7c): Light orange crystalline solid, yield 87%
(4.372 g, crystallization) or 90% (4.523 g, filtration),
m.p. 102–106◦C; refractive index nD22: 1.661. Anal.
Calcd. for C31H26N4O3: C, 74.09; H, 5.21; N, 11.15%.
Found: C, 74.22; H, 5.32; N, 11.11%. IR (cm−1) υ:
3589.1 (OH), 1704.9 (C=N-), 1325.5 (C-N stretching),
1
3438.6 (NH). H NMR (CDCl3, 400 MHz, δ ppm, J
Hz): 10.18 (s, 1H, quinoline -OH); 7.44–8.18 (m, 5H,
quinoline-H); 7.05 (s, 1H sec. amine -NH); 6.78–7.96
(m, 4H, Ar-H); 11.58 (s, 1H, -NH hydrazide); 2.32(s,
3H, -CH3); 7.52–7.94 (m, 5H, Ar-H); 5.59 (s, 1H,
methine); 9.66 (s, 1H, Ar-OH); 6.79–7.09 (m, 4H, Ar-
H). 13C NMR (CDCl3, 75 MHz, ppm) δC : 16.8, 50.1,
112.4, 116.6, 119.6, 120.2, 121.0, 121.4, 121.6, 121.8,
127.6, 128.2, 128.4, 128.8, 130.4, 131.2, 131.3, 135.5,
137.3, 137.5, 147.7, 148.5, 150.4, 151.2, 157.9, 163.3.
MS, m/z: 502 (M+, 100%).
2.3f Nꢁ-[(1)-(2-chlorophenyl)methylidene]-4-{[furan-
2-yl(8-hydroxyquinolin-7-yl)methyl] amino}benzohydrazide
(7f): Light brown crystalline solid, yield 97% (4.82 g,
crystallization) or 99% (4.919 g, filtration), m.p. 96–
98◦C; refractive index nD22: 1.674. Anal. Calcd. for
C28H21 ClN4O3: C, 67.67; H, 4.26; Cl, 7.13; N, 11.27%.
Found: C, 67.74; H, 4.38; N, 11.23%. IR (cm−1) υ:
3536.7 (OH), 1339.4 (C-N stretching), 3125.5 (N–H),
1
1719.2 (C=N-), 1233.6 (COC), 1098.2 (C–Cl). H
2.3d 4-{[(2-chloroquinolin-3-yl)(8-hydroxyquinolin-
7-yl)methyl]amino}-Nꢁ-(furan-2-ylmethylidene)benzo-
hydrazide (7d): Dark brown amorphous solid, yield
94% (5.151 g, crystallization) or 98% (5.37 g, filtra-
tion), m.p. 142–146◦C; refractive index nD22: 1.705.
Anal. Calcd. for C31H22ClN5O3: C, 67.94; H, 4.05; Cl,
6.47; N, 12.78%. Found: C, 67.98; H, 3.96; Cl, 6.49;
N, 12.72%. IR (cm−1) υ: 3103.5(OH), 1625.1 (C=N-),
1333.5 (C-N stretching), 3442.1 (N–H), 1065.3 (Cl).
1H NMR (CDCl3, 400 MHz, δ ppm, J Hz): 9.08 (s,
1H, quinoline -OH); 7.36–8.22(m, 5H, quinoline-H);
7.28 (s, 1H sec. amine -NH); 7.05–7.88 (m, 4H, Ar-H);
7.95 (s, 1H, HN-hydrazide); 7.25 (s, 1H, methylene);
7.24–7.35 (m, 3H, furan-H); 4.56 (s, 1H, methine);
7.32–7.47 (m, 5H, chloroquinolin-H). 13C NMR
(CDCl3, 75 MHz, ppm) δC : 50.9, 112.3, 112.7, 118.9,
120.3, 120.9, 121.2, 121.3, 126.6, 127.1, 127.3, 127.5,
127.6, 128.4, 129.9, 130.2, 131.2, 134.6, 135.5, 136.2,
137.3, 144.5, 145.4, 148.6, 149.2, 150.0, 151.2, 152.3,
164.2. MS, m/z: 547 (M+, 100%).
NMR (CDCl3, 400 MHz, ppm, J Hz) δH : 8.23 (s, 1H,
quinoline-OH); 7.36–8.21 (m, 5H, quinoline-H); 7.38
(s, 1H sec. amine HN-); 7.34–7.41 (m, 4H, Ar-H); 9.09
(s, 1H, hydrazide-NH); 7.46 (s, 1H, methylene); 7.33–
7.45 (m, 4H, Ar-H); 7.25 (s, 1H, methine); 7.32–7.37
(m, 3H, furan-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 58.3, 106.8, 110.7, 112.2, 120.2, 120.9, 121.2,
121.3, 126.9, 127.2, 127.6, 128.4, 130.1, 130.2, 132.4,
133.9, 134.7, 135.5, 137.3, 138.8, 142.2, 148.5, 150.2,
151.4, 152.4, 163.5. MS, m/z: 496 (M+, 100%).
2.3g Nꢁ-[(1)-(2-chloroquinolin-3-yl)methylidene]-4-
{[furan-2-yl(8-hydroxyquinolin-7-yl) methyl]amino}benzo-
hydrazide (7g): Light brown crystalline solid, yield
91% (4.986 g, crystallization) or 93% (5.096 g, filtra-
tion), m.p. 221–224◦C; refractive index nD22: 1.705.
Anal. Calcd. for C31H22 ClN5O3: C, 67.94; H, 4.05; Cl,
6.47; N, 12.78%. Found: C, 68.18; H, 4.24; Cl, 4.52;
N, 12.82%. IR (cm−1) υ: 3350.4 (OH), 1327.2 (C-N
stretching), 3413.9 (N-H), 1698.9 (C=N-), 1233.8
1
(COC), 1068.3 (C–Cl). H NMR (CDCl3, 400 MHz,
2.3e 7-[Furan-2-yl({[(3)-3-[2-[(2-hydroxy-3-methoxy-
phenyl)methylidene]hydrazin-1-ylidene]-1,5-dimethyl-
2-phenyl-2,3-dihydro-1H-pyrazol-4-yl]amino})methyl]
quinolin-8-ol (7e): Dark brown amorphous solid,
yield 86% (4.941 g, crystallization) or 90% (5.171 g,
filtration), m.p. 162–164◦C; refractive index nD22:
1.670. Anal. Calcd. for C33H30N6O4: C, 68.98; H, 5.26;
N, 14.63%. Found: C, 69.12; H, 5.32; N, 14.65%. IR
ppm, J Hz) δH : 8.82 (s, 1H, quinoline-OH); 7.36–8.19
(m, 5H, quinoline-H); 7.39 (s, 1H sec. amine HN-);
7.34–7.44 (m, 4H, Ar-H); 10.01 (s, 1H, hydrazide-
NH); 8.18 (s, 1H, methylene); 7.64–7.97 (m, 5H,
chloroquinolin-H); 7.25 (s, 1H, methine); 7.32–7.36
(m, 3H, furan-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 58.6, 107.1, 110.8, 112.4, 120.2, 120.9, 121.2,

1580
K M Khandarkar et al.
121.3, 124.2, 126.8, 127.2, 127.6, 127.8, 128.1, 128.4, 1338.2 (C-N stretching), 3429.6(NH), 1751.2 (C=N-),
1
130.2, 131.4, 135.7, 137.5, 137.9, 142.1, 143.3, 148.5, 1701.8 (CO). H NMR (CDCl3, 400 MHz, δ ppm, J
149.7, 150.2, 151.3, 152.5, 152.8, 163.2. MS, m/z: 547 Hz): 9.82 (s, 1H, quinoline -OH); 7.42–8.88 (m, 5H,
(M+, 100%).
quinoline-H); 7.63 (s, 1H sec. amine -NH); 6.70–7.68
(m, 4H, Ar-H); 12.11 (s, 1H, hydrazide-NH); 8.52 (s,
1H, methylene); 7.52–7.83 (m, 5H, Ar-H); 7.28–8.04
(m, 10 H, Ar-H). 13C NMR (CDCl3, 75 MHz, ppm) δC :
75.3, 112.4, 120.2, 120.9, 121.2, 121.3, 126.4, 127.7,
128.2, 128.4, 128.6, 128.8, 129.2, 130.2, 131.1, 133.1,
133.7, 135.6, 136.7, 137.3, 140.2, 146.8, 148.5, 150.2,
151.4, 163.2, 196.6. MS, m/z: 576 (M+, 100%).
2.3h 4-{[Furan-2-yl(8-hydroxyquinolin-7-yl)methyl]
amino}-Nꢁ-[(1)-furan-2-ylmethylidene]benzohydrazide
(7h): Brown amorphous solid, yield 94% (4.253 g,
crystallization) or 97% (4.388 g, filtration), m.p. 130–
134◦C; refractive index nD22: 1.679. Anal. Calcd. for
C26H20N4O4: C, 69.02; H, 4.46; N, 12.38%. Found: C,
68.98; H, 4.49; N, 12.34%. IR (cm−1) υ: 3537.4 (OH),
1340.0 (C-N stretching), 3124.9 (N-H), 1719.8 (C=N-),
2.3k 4-({[(4-Hydroxy-3,5-dimethoxyphenyl)(7-hydroxy-
4-methyl-2-oxo-2H-chromen-8-yl) methyl]amino}methyl)-
Nꢁ-[(1)-(2-hydroxyphenyl)methylidene]benzohydrazide
(7k): Orange needlshape solid, yield 91% (5.419 g,
crystallization) or 96% (5.717 g, filtration), m.p. 102–
106◦C; refractive index nD22: 1.646. Anal. Calcd. for
C33H29N3O8: C, 66.55; H, 4.91; N, 7.06%. Found: C,
66.67; H, 5.08; N, 6.97%. IR (cm−1) υ: 3628.9 (OH),
1605.4 (CO), 1346.7 (C-N stretching), 3443.6. (NH),
1
1235.7(COC). H NMR (CDCl3, 400 MHz, ppm, J
Hz) δH : 8.72 (s, 1H, quinoline-OH); 7.36–7.47 (m, 5H,
quinoline-H); 8.23 (s, 1H sec. amine HN-); 7.34–7.43
(m, 4H, Ar-H); 10.81 (s, 1H, hydrazide-NH); 8.45 (s,
1H, methylene); 6.52–7.75 (m, 3H, furan-H); 7.28 (s,
1H, methine); 6.38–7.37 (m, 3H, furan-H). 13C NMR
(CDCl3, 75 MHz, ppm) δC : 28.6, 106.8, 110.7, 112.2,
112.6, 118.8, 120.2, 120.9, 121.2, 121.3, 127.6, 128.4,
130.2, 134.6, 135.6, 137.4, 142.1, 144.4, 148.6, 149.3,
150.1, 151.2, 152.5, 163.4. MS, m/z: 452 (M+, 100%).
1
1746.7 (C=N-), 2816.3 (OCH3). H NMR (CDCl3,
400 MHz, ppm, J Hz) δH : 10.18 (s, 1H, coumarin-
OH); 2.39 (s, 3H, methyl coumarin); 6.26–7.38 (m, 3H,
coumarin-H); 6.59 (s, 1H, sec. amine -NH); 6.38–7.54
(m, 4H, Ar-H); 13.62 (s, 1H, hydrazide-NH); 8.78 (s,
1H, methylene); 12.06 (s, 1H, Ar-OH); 7.02–7.64 (m,
4H, Ar-H); 6.01 (s, 1H, methine); 6.32 (s, 2H, Ar-H);
3.90 (s, 6H, -OCH3); 9.22 (s, 1H, Ar-OH). 13C NMR
(CDCl3, 75 MHz, ppm) δC :, 18.9. 51.2, 56.4, 106.2,
112.2, 112.5, 112.6, 113.2, 117.8, 118.6, 121.2, 121.4,
123.2, 123.7, 127.5, 130.2, 132.5, 135.0, 137.3, 146.0,
147.9, 151.1, 152.7, 154.9, 157.4, 160.9, 163.3. MS,
m/z: 595 (M+, 100%).
2.3i Nꢁ-[1-(4-Aminophenyl)ethylidene]-4-{[chloro(8-
hydroxyquinolin-7-yl)(4-nitrophenyl)methyl]amino}
benzohydrazide (7i): Dark yellow amorphous solid,
yield 89% (5.171 g, crystallization) or 92% (5.345 g,
filtration), m.p. 120–124◦C; refractive index nD22:
1.687. Anal. Calcd. for C31H25ClN6O4: C, 64.08; H,
4.34; Cl, 6.10; N, 14.46%. Found: C, 63.99; H, 4.29;
Cl, 6.15; N, 14.51%. IR (cm−1) υ: 3483.4 (OH), 1347.9
(C-N stretching), 3362.3 (N–H), 3489.5 (aromatic
-NH2), 1721.1 (C=N-), 762.1 (C–Cl), 1459.7 (NO2).
1H NMR (CDCl3, 400 MHz, δ ppm, J Hz): 9.68 (s,
1H, quinoline -OH); 7.42–7.56(m, 5H, quinoline-H);
7.22 (s, 1H sec. amine -NH); 6.25–6.61 (m, 4H, Ar-H);
10.17 (s, 1H, hydrazide-NH); 2.32 (s, 3H, CH3); 6.68–
7.50 (m, 4H, Ar-H), 5.32 (s, 2H, -NH2); 7.99–8.28 (m,
4H, Ar-H). 13C NMR (CDCl3, 75 MHz, ppm) δC : 17.1,
81.2, 112.4, 114.2, 120.2, 120.9, 121.2, 121.3, 124.5,
126.7, 127.5, 128.4, 129.1, 130.2, 130.6, 135.5, 137.4,
145.4, 147.7, 148.5, 149.1, 150.1, 150.7, 151.2, 163.2.
MS, m/z: 580 (M+, 100%).
2.3l 8-[Furan-2-yl({2-[(1)-1-[2-[(2)-3-phenylprop-2-
en-1-ylidene]hydrazin-1-ylidene]ethyl]-1H-pyrrol-1-yl})
methyl]-7-hydroxy-4-methyl-2H-chromen-2-one (7l):
Brown amorphous solid, yield 92% (4.522 g, crys-
tallization) or 95% (4.669 g, filtration), m.p. 136–
140◦C; refractive index nD22: 1.632. Anal. Calcd. for
C30H25N3O4: C, 73.30; H, 5.13; N, 8.55%. Found: C,
73.51; H, 5.24; N, 8.46%. IR (cm−1) υ: 3463.7 (OH),
1663.52 (cyclic CO), 1359.1 (C-N stretching), 1715.8
1
(C=N-), 1623.5 (C=C). H NMR (CDCl3, 400 MHz,
ppm, J Hz) δH : 9.62 (s, 1H, coumarin-OH); 2.14 (s,
3H, methyl coumarin); 6.13–7.98 (m, 3H, coumarin-
H); 2.10 (s, 3H, methyl-H); 6.26–7.81 (m, 3H,
pyrrol-H); 7.50 (s, 1H, methylene); 6.84–6.90 (m, 1H,
ethylene-H); 7.12 (d, 1H, J = 4.4, ethylene -H); 7.28–
7.62 (m, 5H, Ar-H); 6.55 (s, 1H, methine); 6.08–7.60
(m, 3H, furan-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 15.6, 20.0, 48.2, 106.8, 108.7, 110.2, 110.6, 112.0,
2.3j 4-{[1-(8-Hydroxyquinolin-7-yl)-2-oxo-1,2-diphenyl-
ethyl]amino}-Nꢁ-[(1)-phenylmethylidene]benzohydrazide
(7j): Dull yellow crystalline solid, yield 88% (5.074 g,
crystallization) or 89% (5.132 g, filtration), m.p. 110–
114◦C; refractive index nD22: 1.654. Anal. Calcd. for
C37H28N4O3: C, 77.07; H, 4.89; N, 9.72%. Found: C,
77.21; H, 5.04; N, 9.61%. IR (cm−1) υ: 3518.4 (OH),

Tailored Betti’s product and their click hydrazones
1581
112.5, 117.7, 119.9, 122.1, 122.8, 123.3, 128.0, 128.5, (5.199 g, crystallization) or 89% (5.318 g, filtration),
128.6, 133.4, 135.2, 142.1, 151.8, 152.5, 152.7, 155.7, m.p. 111–114◦C; refractive index nD22: 1.661. Anal.
157.3, 160.8, 165.6. MS, m/z: 491 (M+, 100%).
Calcd. for C36H27N3O6: C, 72.35; H, 4.55; N, 7.03%.
Found: C, 72.22; H, 4.49; N, 6.96%. IR (cm−1) υ:
3462.3 (OH), 1715.0 (cyclic CO), 3437.1 (NH), 1349.8
(C-N stretching), 1689.7 (C=N-), 1672.8 (C=C). H
2.3m 7-Hydroxy-8-({2-[(1)-1-[2-[(2-hydroxyphenyl)
methylidene]hydrazin-1-ylidene]ethyl]-1H-pyrrol-1-yl}
(4-methoxyphenyl)methyl)-4-methyl-2H-chromen-2-one
(7m): Orange crystalline solid, yield 90% (4.694 g,
crystallization) or 92% (4.798 g, filtration), m.p. 113–
116◦C; refractive index nD22: 1.637. Anal. Calcd. for
C31H27N3O5: C, 71.39; H, 5.22; N, 8.06%. Found: C,
71.48; H, 5.31; N, 8.00%. IR (cm−1) υ: 3536.6 (OH),
1646.8 (cyclic CO), 1356.6 (C-N stretching), 2841.7
1
NMR (CDCl3, 400 MHz, ppm, J Hz) δH : 10.38 (s,
1H, coumarin-OH); 1.96 (s, 3H, methyl coumarin);
6.22–7.44 (m, 3H, coumarin-H); 4. 96 3.98 (s, 1H sec.
amine HN-); 6.74–7.56 (m, 4H, Ar-H); 11.08 (s, 1H,
hydrazide-NH); 7.58 (s, 1H, methylene); 6.85 (m, 1H,
ethylene); 7.22 (d, 1H, ethylene, J = 8.2); 7.30–7.62
(m, 5H, Ar-H); (s, 1H, methine); 6.30–8.10 (m, 5H,
chromon-H). 13C NMR (CDCl3, 75 MHz, ppm) δC :
19.6, 53.5, 109.9, 111.9, 112.2, 112.4, 112.5, 116.3,
121.2, 122.5, 123.4, 123.8, 124.6, 125.9, 126.4, 127.9,
128.6, 128.6, 130.3, 134.1, 135.4, 137.3, 149.5, 149.9,
152.7, 153.6, 157.2, 160.8, 163.4, 167.3, 178.2. MS,
m/z: 597 (M+, 100%).
1
(OCH3), 1723.8 (C=N). H NMR (CDCl3, 400 MHz,
ppm, J Hz) δH : 9.83 (s, 1H, coumarin-OH); 2.39 (s,
3H, methyl coumarin); 6.23–7.42 (m, 3H, coumarin-
H); 2.10 (s, 3H, methyl-H); 6.23–7.37;(m, 3H, pyrrol-
H); 8.72 (s, 1H, methylene); 11.64 (s, 1H, Ar-OH);
7.22–7.96 (m, 4H, Ar-H); 6.16 (s, 1H, methine); 3.78
(s, 3H, methoxy-H); 6.88–7.10 (m, 4H, Ar-H). 13C
NMR (CDCl3, 75 MHz, ppm) δC : 15.4, 19.6, 55.4,
56.1, 108.7, 110.2, 112.4, 112.6, 113.2, 114.8, 117.8,
118.6, 121.4, 122.2, 122.8, 123.0, 123.6, 129.3, 129.8,
132.1, 132.4, 151.0, 152.7, 154.9, 157.3, 158.4, 160.8,
161.1, 164.7. MS, m/z: 521 (M+, 100%).
2.3p 4-{[(7-Hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)
diphenylmethyl]amino}-Nꢁ-[(1)-(4-methoxyphenyl)
methylidene]benzohydrazide (7p): Bright yellow
crystalline solid, yield 83% (5.06 g, crystallization)
or 87% (5.3 g, filtration), m.p. 122–126◦C; refractive
index nD22: 1.634. Anal. Calcd. for C38H31N3O5: C,
74.86; H, 5.13; N, 6.89%. Found: C, 74.98; H, 5.30; N,
6.78%. IR (cm−1) υ: 3478.9 (OH), 1714.6 (cyclic CO),
3451.2 (NH), 1347.6 (C-N stretching), 1738.9 (C=N-),
2.3n 8-[(2-Chloroquinolin-3-yl)[(4-{2-[2-[(3-nitrophenyl)
methylidene]hydrazin-1-yl]acetyl} phenyl)amino]methyl]-
7-hydroxy-4-methyl-2H-chromen-2-one (7n): Yellow
amorphous solid, yield 86% (5.469 g, crystallization)
or 90% (5.724 g, filtration), m.p. 104–108◦C; refractive
index nD22: 1.703. Anal. Calcd. for C34H24ClN5O6: C,
64.41; H, 3.82; Cl, 5.59; N, 11.05%. Found: C, 64.54;
H, 3.45; Cl, 5.63; N, 10.89%. IR (cm−1) υ: 3508.2
(OH), 1714.9 (cyclic CO), 3421.9 (NH), 1289.6 (C-N
stretching), 1742.3 (C=N-), 1097.9 (C–Cl), 1335.8
1
2836.5 (OCH3). H NMR (CDCl3, 400 MHz, ppm,
J Hz) δH : 10.36 (s, 1H, coumarin-OH); 2.32 (s, 3H,
methyl coumarin); 6.28–7.46 (m, 3H, coumarin-H);
6.02 (s, 1H sec. amine HN-); 6.72–7.54 (m, 4H, Ar-H);
12.81 (s, 1H, hydrazide-NH); 8.18 (s, 1H, methylene);
7.06–7.84 (m, 4H, Ar-H); 3.83 (s, 3H, -OCH3); 7.21–
7.43 (m, 10H, Ar-H). 13C NMR (CDCl3, 75 MHz, ppm)
δC : 19.7, 59.6, 112.2, 112.4, 112.6, 113.2, 114.4, 121.2,
123.1, 123.8, 126.0, 126.2, 127.0, 129.3, 130.3, 145.0,
146.8, 151.1, 152.7, 154.9, 160.8, 162.9, 163.7. MS,
m/z: 609 (M+, 100%).
1
(NO2). H NMR (CDCl3, 400 MHz, ppm, J Hz) δH :
12.21 (s, 1H, coumarin-OH); 2.38 (d, 3H, methyl
coumarin); 6.22–7.48 (m, 3H, coumarin-H); 6.28 (s,
1H, sec. amine -NH); 6.72–7.56 (m, 4H, Ar-H); 9.88
(s, 1H, hydrazide-NH); 9.16 (s, 1H, methylene); 7.78–
8.52 (m, 4H, Ar-H); 5.78 (s, 1H, methine); 7.51–8.96
(m, 5H, quinoline-H). 13C NMR (CDCl3, 75 MHz,
ppm) δC : 19.5, 45.4, 112.2, 112.5, 112.7, 113.3, 121.2,
121.6, 123.0, 123.6, 123.8, 126.2, 126.6, 127.6, 128.4,
129.7, 130.3, 131.8, 132.6, 134.6, 136.1, 138.7, 141.0,
146.3, 148.5, 150.6, 151.0, 152.7, 154.9, 160.9, 163.2.
MS, m/z: 633 (M+, 100%).
3. Results and discussion
In view of emerging importance of green synthesis and
our general interest in solid acid catalysed chemical
reactions, we envision expedited Betti’s reactions using
zeolites as catalysts. Both natural and synthetic zeo-
lites are used as a catalyst to extend the Betti’s reaction
towards the greener protocol.
2.3o 7-Hydroxy-4-methyl-8-[(4-oxo-4H-chromen-2-yl)
[(4-{2-[2-[(2)-3-phenylprop-2-en-1-ylidene]hydrazin-
1-yl]acetyl}phenyl)amino]methyl]-2H-chromen-2-one
Initially we focused on the synthesis of β-
aminoheteronapthol from aromatic carbonyl com-
(7o): Light yellow amorphous solid, yield 87% pound, amine and 8-hydroxy quinoline or coumarin.

1582
K M Khandarkar et al.
Ar2
Ar1
(5)
OH
NH
3.1 Chemistry
R
N
Ar3OH
(3)
The Betti’s classical procedure, a Mannich-type
aminoalkylation condensation of 2-naphthol and aro-
matic aldehyde in the presence of ammonia, was
modified by condensing carbonyl compound (1), aro-
matic amine (2) and heteronapthol [here, 8-hydroxy
quinolone (3) or 7-hydroxy-4-methyl-coumarin (4)]
in the presence of zeolite to prepare the β-
aminoheteronapthol (5/6) (scheme 1).
Zeolite/ EtOH
Ar2 NH2
(2)
Ar1COR
R
(1)
Ar2
O
Ar1
HO
Ar4OH
(4)
N
H
O
O
O
N
Ar4 =
(6)
R= H, Cl, Aryl
Ar3 =
CH3
The natural zeolite applied here are scolecite
(CaAl2Si3O.103H2O), stilbite (NaCa4 (Si27Al9)O.72 28(H2O)),
fluorapophyllite (KCa4Si8O20(F,OH)·8(H2O)) and meso-
lite (Na2Ca2(Al2Si3O10)3 ·8H2O) and synthetic zeolite
are crystalline molecular sieves which can be repre-
Scheme 1. Zeolite catalysed tailored Betti’s condensation.
Most of the earlier proposed procedures for the pro- sented by general formula −M2/nO[(AI2O3).(SiO2)X].y
duction of Mannich-base involve various organic and H2O, where M represents alkali metals with valency-n.
mineral acid catalysed reaction conditions. The synthe- These aluminosilicates are 3A, 4A, 5A and 13X with
sis of these compounds was reported by performing pore size 3 Å, 4 Å, 5 Å and 10 Å, respectively. The
the reaction in the presence of Lewis acid,31 Bronsted alkali metal in aluminosilicate 3A and 4A is potassium,
acid catalysts,32 Lewis base,33 transition metal salt34 5A is calcium and 13A is sodium. A detailed study on
catalysts condition and even uncatalysed one-pot, three- catalyst standardization is obtained from the chemical
component synthesis of Betti’s base in water.35 How- oxide-form composition of the zeolitic raw minerals as
ever, all of these chemical processes required reflux- shown in table 1.
ing for extensive reaction time, large quantities of
In present work of modified Betti’s reaction product
mineral or Lewis acids as activators which on work- synthesis, use of zeolite catalyst reduces the time period
up are hydrolysed with generation of large quanti- of reaction with the yield of 92%–98% and the catalyst
ties of corrosive and toxic waste by-products, long was recovered completely which was reused in three
reaction time (days) along with purification steps and consecutive reactions having more than 90% yield. The
the uncatalysed Betti’s reaction involves only basic products of modified Betti’s reaction are specified in
2-pyridinyl, 2-pyrazinyl and 2-pyrimidinyl amine as table 2.
amine moiety which act as a catalyst.
The catalyst was cleanly separated after completion
Here, we wish to disclose our results, studying the of the reaction (monitored by TLC) by simple filtration
application of natural and synthetic zeolite as a catalyst in hot condition. The obtained solid condensation pro-
in synthesis of some novel and bioactive Betti’s reac- duct was further purified by recrystallization in ethanol.
tion product and their hydrazone (arylidenehydrazine) As the granular size of the zeolite is used, 100%
derivatives by, catalyst-free most placid reaction condi- recovery of the catalyst is possible even after three
tion of click synthesis in least amount of solvent.
consecutive runs. And it was found that the recovered
Table 1. Oxide-form chemical composition of the raw mineral, natural zeolites and molecular
sieves in weight %.
Catalyst
SiO2
Al2O3
CaO
Na2O
K2O
H2O
F
Total
Fluorapophyllite
Scolecite
Stilbite
Mesolite
Molecular sieves
3A
4A
5A
13X
51.98
45.16
52.70
46.98
0.36
25.90
17.71
26.43
25.10
14.86
7.76
0.61
0.16
2.39
4.57
4.45
0.06
1.09
0.05
16.25
13.66
18.40
11.94
2.20
100.03
99.80
100.05
100.03
–
–
–
10.06
41.45
47.50
40.16
48.59
19.68
23.75
20.58
16.97
–
–
3.58
4.75
6.37
8.74
18.87
18.5
24.0
14.63
25.73
–
–
–
–
100.08
100.00
100.06
100.03
–
–
–
18.32
–

Tailored Betti’s product and their click hydrazones
1583
Table 2. Tailored Betti’s reaction between carbonyl compound, amine and heteronapthol (here, quinoline/chromene)a.
R
H
Ar2
Ar1
Ar1
HO
Ar2
O
OH
NH
N
R
Ar2 NH2
(2)
Ar1COR
(1)
Zeolite/EtOH
Zeolite/EtOH
N
O
Ar3OH
(3)
Ar4OH
(4)
(6)
(5)
O
O
N
Ar3 =
Ar4 =
R=H, Cl, Aryl
CH3
Reaction Yieldb
time (min) (%)
Entry
Ar2NH2
Ar1COR
Product/Compound
O
HO
N
NH
OH
O
C2H5O
O
OHC
NH2
1
CH3
60
96
5a
OH
C2H5O
O
H3C
O
HO
N
NH
OHC
O
H3C
O
CH3
NH2
2
3
90
60
93
97
5b
5c
H3C
OH
HO
O
CH3
HO
C2H5O
O
N
HO
NH
O
NH2
OHC
C2H5O
OH
O
C2H5O
Cl
N
O
NH2
NH OH
4
5
105
120
92
95
5d
5e
C2H5O
OHC
N
N
Cl
N
HO
N
N
O
H
O
O
CHO
CHO
N
NH2
N
O
N
O
O
HO
N
NH
O
C2H5O
NH2
6
7
90
98
97
5f
C2H5O
O
O2N
Cl
O
O
O
NH2
NO2
120
5g
NH
HO
C2H5O
Cl
C2H5O
N

1584
K M Khandarkar et al.
Table 2. (Continued).
N
O
O
HO
NH
O
O
O
C2H5O
NH2
8
120
105
91
5h
C2H5O
OH
O
H
N
NH2
9
93
94
5i
N
HO
OH
CHO
H
N
N
N
N
N
10
90
5j
N
CH3
OH
N
N
O
NH2
N
N
OH
CH3
O
OH
O
O
HO
O
CHO
OH
NH
O
NH2
11
90
95
6a
H3C
CH3
C2H5O
O
O
HO
O
H3C
O
HO
H3C
O
O
H
O
O
N
N
CHO
12
13
90
87
90
6b
6c
O
O
OH
H
N
HO
O
O
O
OCH3
OHC
105
N
O
OCH3
O
O
O
Cl
N
O
NH
NH2
C2H5O
14
105
96
6d
C2H5O
OHC
OH
Cl
N

Tailored Betti’s product and their click hydrazones
1585
Table 2. (Continued).
O
HO
NH
O
OHC
O
O
C2H5O
O
NH2
15
120
90
6e
O
O
O
C2H5O
HO
O
C2H5O
NH2
O
16
150
120
92
95
6f
C2H5O
O
O
O
NH
HO
O
N
O
O
CHO
17
6g
NH
O
O
O
aAll reactions were performed in EtOH at 40◦C in the presence of natural/synthetic zeolite as a catalyst. The solid obtained
from the reactions was purified by washing with cold EtOH and by recrystallization in MeOH/EtOH
bOf pure and isolated product
catalyst shows almost same yield with three successive were obtained in excellent yields for all the investigated
reactions (table 3). The recovered catalyst was washed substrates (85–97%), regardless of the nature and posi-
with ethyl acetate, then dried at 70◦C prior to use tion of the substituents and/or hetero aromatic nature
for next run in model reaction and activated at 350◦C of the carbonyl compound. In any case, reactions take
after three consecutive runs. The activity of the catalyst a longer time to reach completion for these more chal-
decreases after fourth run plausibly due to impediment lenging substrates (2–2.5 h) as compared to aldehydes,
of pores of the zeolite.
which provide quantitative conversion to products in
Interestingly, the addition of 0.5 g catalyst was found 0.5–2 h of reaction. A series of optimization experi-
to be sufficient to provide excellent yields of pro- ments pointed to a remarkable acceleration of reaction
ducts (<90%) after moderately short reaction time (typi- rates and therefore yields, at slightly increased reaction
cally between 1 and 3 h). Lower catalyst loading and temperatures. Temperatures as low as 40◦C provided
reaction time (less than 30 min) at room temperature almost quantitative yields of products at reduced reac-
turned out to be inefficient and resulted in significantly tion times (ranging from 1 to 2 h; table 2) by employing
reduced yields (85% and below). The protocol was also zeolite as catalyst. Yields were somewhat reduced for
amenable to a range of substrates, including different substrates with larger chains, but in any case the devised
aldehydes as well as more challenging substrates, such protocol was suitable for both aromatic and aliphatic
as ketone and benzoyl chloride (table 2). The products (cyclic and acyclic) substituents. The time period of
reaction decreases with further increase in temperature
(from 50 to 70◦C) but did not have much influence on
Table 3. Recovery and reusability of catalysts.a
the yields of products as compared to those at 40◦C
(table 4). But when compared to other catalysts, zeolites
afford a much reduced reaction period with promis-
ingly greater yield and a complete green sustainable
technique.
Mannich-base, Catalyst recovery
Entry
Cycle
% yield
% weight
1
2
3
4
5
Fresh
99
99
98
97
95
100%
100%
100%
100%
100%
1st recycle
2nd recycle
3rd recycle
4th recycle
3.1a Bis-aryl hydrazones: Synthesis of these
hydrazides, hydrazones and their derivatives involves
strong acid catalysed reaction condition of multiple
steps of hours or overnights reflux in abundant sol-
vent.36 These harsh reaction conditions and hazardous
aReaction condition: carbonyl compound: amine:
quinoline/chromene, 1:1:1 (mol ratio), natural zeolite =
stilbite (0.5 g crystalline), temperature = 40◦C

1586
K M Khandarkar et al.
A plausible mechanism is proposed for the acid
catalysed condensation of carbonyl compound, amine
and heteronapthol to give β-amino-phenol using zeo-
lite (scheme 3). The carbonyl compound (1) combines
with the amine (2) in mild acidic medium provided by
Table 4. The effect of reaction temperature on the activity
of zeolite for the Betti’s condensation of carbonyl compound,
amine and quinoline/chromene (5/6).
Temperature ◦C
Yield (%)
Time (min)
25
90
180
30
93
150
40
94
95
50
97
75
60
99
60
70
99
50 zeolite to give (A) which on dehydrolysis provides sta-
ble electrophile iminium ion (B). The heteronapthol (C)
functions as a very good carbon nucleophile, giving the
intermediate represented by the resonance structures,
which subsequently loses a proton to furnish β-amino-
phenol. It is easy to identify from this mechanism that
acid catalysis aid the reaction and indeed increased rates
with greener approach have been observed using zeolite
catalysis.
Reaction conditions: 1 mmol quinoline/chromene, 1 mmol
substrate amine and carbonyl compound, 0.5 g zeolite, with
stirring
catalyst, solvent and byproducts were utterly removed
here by carrying out the reaction in limited amount
of solvent without catalyst using principle of click
reaction which is wide scope, high yielding and stereo-
specific with high atom economy.22–25 The hydrazone
moiety was selected for its high stability at physiologi-
cal pH, and liability under strongly acidic and basic
3.2 In vitro antimicrobial screening
conditions as demonstrated by drug delivery agents in A chemical library of the compounds from the series
tumour targeting.37,38 To our knowledge, such catalyst- 5a–5j, 6a–6g and 7a–7p were tested for antimicrobial
and solvent-free Betti’s bis-arylhydrazone click product and antifungal activity. The fungal and bacterial cul-
has not yet been explored.
tures were kindly provided by Rajiv Gandhi Biotech-
In the present work, we mixed equimolar quantities nology Centre, Nagpur. Agar well diffusion method
of hydrazine hydrate 80%, β-aminoheteronapthol (5/6) was used to determine the antibacterial activity of these
(solubilized in minimum ethanol) and aromatic aldehy- compounds, with amoxicillin and gentamicin as the
des together in a petri dish at room temperature with standard antimicrobial agents and nystatin and flucana-
the help of a glass rod. Surprisingly, the reaction started zol as the standard antifungal agents. For the diffusion
immediately after mixing and a shiny immense hydra- well method, the solvent used was dimethylsulphoxide
zone product appeared within a few seconds with gen- (DMSO) and its antimicrobial activity against all the
tle heat production, scheme 2. The progress of the reac- proposed pathogenic microbial cultures was found too
tion and by-products was monitored by thin-layer chro- negligible to be considered as zero. The concentrations
matography and then the reaction mixture was allowed of the compounds taken were 1, 0.5, 0.25, 0.1, 0.01 and
to stand for 1–2 min to obtain hydrazone product (7) in 0.001 mg/ml in DMSO with 20 μl solution in each well
a complete quantitative yield.
(5 mm diameter hole cut in agar gel).
Excited by the above result, a range of β-
aminoheteronapthol hydrazone derivatives were syn-
thesized by the simple mixing of aromatic aldehyde and 3.2a Test-microbes: The antibacterial activity of
hydrazine hydrate (80%) with β-aminoheteronapthol compound was assessed against pathogenic strains both
just solubilized in ethanol for homogenous reaction Gram-positive and Gram-negative bacteria, the patho-
at room temperature; the results are summarized in genic Gram-positive bacteria for testing were Staphy-
table 5. All the products were obtained in quantitative lococcus aureus, Streptococcus mutants, Bacillus sub-
yield (>85%) in analytically pure form, recrystallized tilis and Gram-negative bacteria were Escherichia coli,
by ethanol/methanol without any further purification.
Pseudomonas aeruginosa, Salmonella typhi, Klebsiella
R1
H 5
2
O
C2H5OH
H2O
C
R2
N
O
=
N
Ar
R
O
H
i
O
H2N NH2
R1
R2
R
Ar
(5/6)
R1
R2
R
2 H2O
N
N
Ar
Scheme 2. Bis-aryl hydrazone derivative via click reaction.

Tailored Betti’s product and their click hydrazones
1587
Table 5. Bis-aryl hydrazones of β-aminoheteronapthol by click reaction.a
R1
O
5
H
H2O
C2H5OH
2
R2
N
OC
N
H
Ar
=
=
O
O
i R
ii R
H2N NH2
R1
R2
R
Ar
(5/6)
CH
R1
R2
R
3
2 H2O
N N
Ar
Reaction
time (s)
Yieldb
(%)
Entry
Compound
R1COR2
Product
F
O
HO
N
NH
F
N
NH
O
1
5a
5b
6
7
90
7a
OH
O
H3C
H3C
HO
N
O
H3CO
NH
O
N
N
2
93
7b
OCH3
HO
H3C
CH3
N
NH
O
HO
N
O
NH
3
4
5c
9
87
94
7c
H3C
OH
HO
O
O
N
NH
O
N
NH
CHO
5d
10
7d
Cl
N
H3C
O
OH
N
HO
CHO
N
N
H
N
OH
CH3
5
6
5e
5f
15
86
97
7e
7f
N
O
N
O
Cl
O
N
N
H
5
Cl
OH
NH
N
O
O

1588
K M Khandarkar et al.
Table 5. (Continued).
N
Cl
O
Cl
N
OHC
N
N
H
7
8
5f
5f
8
9
91
94
7g
7h
OH
NH
N
O
O
O
N
N
H
NH OH
O
CHO
N
O
H2N
CH3
H3C
O
N
NH
O
9
5g
12
89
7i
OH
N
NH2
HN
NO2
Cl
O
HN
N
OH
O
NH
N
10
5h
10
88
7j
O
O
O
H
N
OH
O
H
N
OH
11
12
6a
6b
6
5
91
92
7k
7l
OH
N
O
O
CH3 OH
O
CH3
O
N
O
N
O
O
N
HO
OCH3
O
O
OH
O
13
6c
7
90
7m
N
N
OH
N
OH

Tailored Betti’s product and their click hydrazones
1589
Table 5. (Continued).
O2N
O
N
O
O
N
H
O
NH
14
15
6d
6e
8
7
86
87
7n
7o
NO2
N
Cl
HO
O
HO
NH
O
N
NH
O
O
O
O
O
O
O
16
6f
8
83
7p
H3CO
OH
N
NH
O
OCH3
NH
aReaction condition‘ Mixing of reactants with a spatula in a petri dish for 10–15 s followed by allowing the mixture to stand
for up to 15–30 s if necessary
bOf pure and isolated product
pneumonia. The pathogenic fungi referred for antifun- (mm) formed around the well (NCCLS, 1993). Refer-
gal activity were Aspergillus niger, Phythophthora sp., ence commercial antibacterials used were amoxicillin
Aspergillus flavus, Candida albicans, Rhizopus orazyae and gentamicin and antifungal used were nystatin and
and Fusarium oxysporium. All the microbes were sub- flucanazol. Tests were performed in duplicates and
culture in sterilized nutrient broth.
results were presented in tables 6 and 7.
The compounds 5d, 5f, 5j, 7a, 7d and 7h pro-
vide better antibacterial properties against most of
the pathogenic bacteria compared to standard antibac-
terial, Gentamicin and it has also been found that
these Betti’s reaction product and bisarylhydrazone
are active against Methicillin-resistant Staphylococ-
cus aureus bacterium and certain quinolone resistant
pathogens like S. pyogenes, E. coli, P. aeuruginosa. The
compounds 5a, 5d, 5f, 5j, 6d and 6g demonstrated very
good antifungal results against all the pathogenic fungi
under consideration. The pathogenic Phytophthora sp,
which was not successfully medicated, was also found
to be overawed by these compounds. These potent
products also have the MIC at very low concentration.
3.2b Agar well diffusion method: For the antibacte-
rial efficacy, Muller Hinton agar medium (33.9 g) was
taken in distilled water (1 L) which was autoclaved
at 15 lbs pressure at 121◦C for 15 min and poured
onto 100 mm petriplates (25–30 ml/plate) in molten
state. The antimicrobial efficacy of compounds were
assessed by the mortification of mycelia growth of fun-
gus observed as a zone of inhibition near the well
scratch on Potato Dextrose agar medium. The micro-
bial inoculum (300 μl) was uniformly spread using ster-
ile cotton swab on a sterile Petri dish agar. The 20 μl
solution of compounds of concentration 1, 0.5, 0.25,
0.1, 0.01 and 0.001 mg/ml in DMSO was taken in each
well cut in agar gel plate. The systems were incubated
under aerobic conditions for 24 h at 36◦C
1◦C for
bacterial colony and at 25◦C 1◦C for fungal colonial 3.2c Minimum inhibitory concentration (MIC) deter-
growth. After incubation, confluent microbial growth mination: Certain compounds of the subject have been
was observed. Inhibition of the microbial growth was found to have MIC values (μg/ml) that are up to about
assayed by measuring the diameter of inhibition zone 500 times lower than amoxicillin and ciprofloxacin

1590
K M Khandarkar et al.
Iminium ion formation
Si
Ar1
H
Ar1
O
C
O H
O
C
Al
R
R
(1)
Zeoite
Ar1
Ar1
C
Ar1
H
O
R'
N
R'
R'
H
O
H
Ar2
O
O
C
Ar2
N
Ar2
C
R
N
H
R
H
R
(2)
(A)
Al
Si
Ar1
C
R'
N
Ar1
Ar1
R
H
Ar1
C
R'
R'
R'
H
Si
H
Ar2
C N
O
N
Ar2
O
C
N
O
O H
Al
Zeoite
2
Ar2
iminium ion
(B)
Resonance
H
Ar
R
H
R
R
Proton transfer and -amino hydroxy compound formation
O
O
O
O
O
H
H
Ar
Ar
Ar
Ar
O
Ar
Al
Si
Enolizable carbonyl
compound
(C)
Si
Al
O
H
O
Ar1
R
Ar1
O
R'
O
R'
Ar1
R'
N
Ar2
C
N
C
N
Ar2
Ar
Ar
C
R
R
Ar2
Ar
H
O
Al
Si
OH
Ar1
R'
N
C
R
Ar
Ar2
Scheme 3. Zeolite catalysed mechanism for β-aminoheteronaphthol formation.
and comparable enough to replace gentamicin. More- compared to other substituted benzene and pyrazol
over, invented compound inhibits the antifungal activity
against widespread pathogenic fungi having MIC about
10 times reduced amount of known antifungal agents
like flucanazole. The MIC of the compounds is given in
tables 8 and 9.
The percentage of mycelial growth inhibition (P) for
pathogenic bacteria and fungi was calculated by the for-
mula P = (C − T) / C × 100, where C is the diameter of
the control colony and T that of the treated ones (stan-
dard drug).38 The growth inhibitions of compounds
compared with standard drugs against pathogenic bac-
teria are shown in figure 1 and against pathogenic fungi
are shown in figure 2.
ring. Aliphatic amine (5i) substitution decreases the
antimicrobial activity of Betti’s product. 4-oxo-4H-
chromene and 2-chloroquinoline ring in coumarin
based Betti’s product (6a–6g) also reduces the antibac-
terial activity of the Betti’s product. Presence of both
morpholine and furan ring raise the antibacterial acti-
vity in coumarin based Betti’s compound (6g). The
derivatization (7a–7p) of Betti’s base overall decreases
the antibacterial activity.
Antifungal activity of Betti’s product and their hydra-
zone derivatives are comparable with nystatin but the
quinoline based Betti’s products having 2-chloroqui-
noline (5d) and furan (5f) ring substitution has the
activity over and much above the nystatin. In coumarin-
based Betti’s product, 4-oxo-4H-chromene with benzo-
caine (6e) and furan with morpholine (6g) has effec-
tive antifungal activity. Syringaldehyde coumarin-based
Betti’s product has better antifungal activity compared
3.2d Structure activity relationship (SAR): In
quinoline-based Betti’s product (5a–5j), the furan
(5d), 2-chloroquinolin (5f) and purine (5j) substitu-
tion increases antimicrobial activity tremendously as to hydrazone derivative of the Betti’s products with

Tailored Betti’s product and their click hydrazones
1591
Table 6. Antibacterial efficacy of the compounds (0.25 mg/ml) against pathogenic bacteria.
Zone of inhibition
Gram-positive bacteria
Gram-negative bacteria
Staphylococcus Streptococcus Bacillus Escherichia Pseudomonas Salmonella Klebsiella
Compounds
aureus
mutants
subtilis
coli
aeruginosa
typhi
pneumonia
5a
5b
5c
5d
5e
5f
5g
5h
5i
18
19
29
50
32
68
28
30
16
65
20
22
30
11
–
28
34
31
29
28
–
21
27
26
15
18
23
24
31
30
26
29
14
30
11
12
14
16
42
28
42
10
24
11
35
18
16
22
06
17
22
24
39
36
26
22
16
38
30
45
28
30
27
32
33
26
30
11
37
–
12
13
11
40
19
44
32
17
13
37
14
09
18
08
09
15
20
24
23
26
24
18
31
32
20
23
29
22
25
26
21
24
14
41
18
16
17
20
45
18
60
12
19
–
40
06
14
16
–
10
12
14
22
14
23
16
16
08
18
12
17
18
07
08
18
21
22
16
25
14
11
17
24
15
14
16
14
14
18
12
15
12
19
–
42
24
27
68
39
80
18
40
–
24
08
12
37
–
14
33
28
28
14
31
22
17
18
33
27
18
26
23
25
27
19
22
20
38
–
16
12
23
60
28
65
23
29
14
72
12
18
27
14
18
32
43
27
30
27
25
16
33
29
26
20
25
23
34
29
21
24
19
32
12
5j
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
–
16
41
35
32
30
26
15
34
31
29
17
28
21
26
28
19
26
16
32
10
7m
7n
7o
7p
A
B
A = Gentamicin; B = Amoxicillin; a = the diameters of zone of inhibition were in mm
respect to nystatin but its own salicylaldehyde hydra- Betti’s condensation reaction. A range of carbonyl com-
zone derivative (7k) has least antifungal activity. The pounds and amines could be efficiently reacted with
effective antimicrobial activity of the synthesized com- quinoline/coumarin to give the corresponding substi-
pounds is mainly due to the presence of vicinal amino tuted β-aminoheteronaphthols. Furthermore, we have
hydroxy group in the structure of the compounds.
developed a general, highly efficient, catalyst-free, least
solvent consuming, high yield, step-economic, and eco-
friendly method for the synthesis of bis-aryl hydra-
zones derivatives via the one-pot, three component
coupling click reaction of β-aminoheteronaphthols,
4. Conclusion
An array of biologically and pharmaceutically active hydrazine hydrate and aldehydes/ketones acetate under
novel heterocycles were engendered by tailored Betti’s lenient conditions. The antibacterial and antifungal
reaction with green fundamentals. Natural as well as properties were characterized by zone of inhibition
synthetic zeolite was demonstrated in general to be an and compared with standard drugs. The compounds
efficient and versatile catalyst for the three-component were better antimicrobial agent compared to standards

1592
K M Khandarkar et al.
Table 7. Antifungal efficacy of the compounds (0.25 mg/ml) against pathogenic fungi.a
Zone of inhibition
Aspergillus Phythophthora Aspergillus Candida Rhizopus
Fusarium
Compounds
niger
sp
flavus
albicans orazyae oxysporium
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
27
28
22
60
54
68
24
33
55
30
39
48
45
26
24
23
46
16
16
25
33
28
18
32
36
34
22
24
20
16
20
18
15
22
–
52
51
46
100
–
38
–
38
37
34
51
44
60
23
22
46
42
20
21
30
26
64
46
31
19
30
35
23
21
28
20
22
22
18
14
25
26
20
17
15
25
20
42
44
38
72
51
85
12
18
67
34
33
36
24
27
20
22
43
14
21
19
26
21
22
23
27
27
21
10
24
18
17
14
16
26
–
36
34
–
33
54
48
56
22
26
23
45
38
33
31
36
34
34
38
23
24
19
25
19
23
21
20
16
14
08
19
21
23
16
13
24
–
60
40
100
21
20
54
48
39
34
31
29
28
33
41
18
24
–
26
22
25
24
07
24
20
11
18
21
19
12
17
18
–
100
19
31
62
50
43
41
32
35
78
36
60
21
30
20
28
18
29
26
30
28
16
23
20
24
22
15
27
13
–
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
Nystatin
Flucanazol
a
= the diameters of zone of inhibition were in mm
Table 8. MIC for antibacterial efficacy.a
Gram-positive bacteria
Gram-negative bacteria
Staphylococcus
aureus
Streptococcus
mutants
Bacillus
subtilis
Escherichia
coli
Pseudomonas
aeruginosa
Salmonella
typhi
Klebsiella
pneumonia
Compounds
5d
5f
5j
7a
7d
7h
A
1
1
5
100
500
250
5
1
1
5
50
25
25
0.5
500
1
1
5
100
5
5
1
1
1
50
5
5
5
5
100
250
250
100
5
1
1
100
250
5
5
5
1
1
1
100
5
5
0.5
250
5
250
1
250
B
250
500
500
A = Gentamicin; B = Amoxicillin; a = all the values are in μg/ml

Tailored Betti’s product and their click hydrazones
1593
Table 9. MIC for antifungal efficacy.a
Aspergillus Phythophthora Aspergillus Candida Rhizopus Fusarium
Compounds
niger
sp
flavus
albicans orazyae oxysporium
5a
5d
10
5
10
1
50
1
10
1
10
1
50
1
5f
5j
6d
6g
5
1
5
5
100
25
1
1
5
100
100
1
5
5
50
25
1
5
5
100
10
1
10
50
10
1
10
100
50
1
Nystatin
Flucanazol
100
100
100
10
100
100
a
= all the values are in μg/ml
Figure 1. Growth inhibition of compounds with respect to gentamicin against pathogenic bacteria.
Figure 2. Growth inhibition of compounds with respect to nystatin against pathogenic fungi.
amoxicillin and flucanazol. The compounds 5d, 5f and having better antifungal activity amongst all and MIC
5j were showing very good antibacterial activity against value analogous to nystatin. Thus, these green tech-
maximum pathogenic bacteria with lower MIC than nologically synthesized compounds could be used as
gentamicin and compounds 5d, 5f, 6d and 6g were putative more potent antimicrobial compounds.

1594
K M Khandarkar et al.
Dawson P E 2010 Angew. Chem. 122 2067; (c) Dirksen
Supporting information
A, Dirksen S, Hackeng T M and Dawson P E 2006 J.
Am. Chem. Soc. 128 15602
15. Contelles J M, Mayoral E P and Ballesteros P
2008 Comprehensive heterocyclic chemistry III, Chapter
10.05 (Elsevier Science Limited) pp. 100–306
16. Kumar P, Narasimhan B, Sharma D, Judge V and Narang
R 2009 Eur. J. Med. Chem. 44 1853
Theelectronic supporting information can be seen in
www.ias.ac.in/chemsci.
17. Sherman A R 2008 Comprehensive heterocyclic chem-
istry III, Chapter 10.06 (Elsevier Science Limited)
pp. 263–338
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