Glycerol assisted eco-friendly strategy for the facile synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) and 2-aryl-2,3-dihydroquinazolin-4(1H)-ones under catalyst-free conditions

Article abstract of DOI:10.1007/s11164-016-2728-z

Abstract: This article describes glycerol mediated eco-friendly approaches for the convenient access of structurally diverse 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) and 2-aryl-2,3-dihydroquinazolin-4(1H)-one motifs under catalyst-free conditions. Prominent advantages include clean processes, atom-efficiency, simplicity of the work-up, neutral conditions, low-cost reaction medium, excellent product yield and solvent reusability, in addition to relatively shorter reaction times. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2728-z

Res Chem Intermed
DOI 10.1007/s11164-016-2728-z
Glycerol assisted eco-friendly strategy for the facile
synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-
pyrazol-5-ols) and 2-aryl-2,3-dihydroquinazolin-
4(1H)-ones under catalyst-free conditions
Rathinam Ramesh1 Nagarajan Nagasundaram1
•
•
Durairaj Meignanasundar1 Pullar Vadivel2
Appaswami Lalitha1
•
•
Received: 27 June 2016 / Accepted: 1 September 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract This article describes glycerol mediated eco-friendly approaches for the
convenient access of structurally diverse 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-
5-ol) and 2-aryl-2,3-dihydroquinazolin-4(1H)-one motifs under catalyst-free conditions.
Prominent advantages include clean processes, atom-efficiency, simplicity of the work-
up, neutral conditions, low-cost reaction medium, excellent product yield and solvent
reusability, in addition to relatively shorter reaction times.
Graphical Abstract
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2728-z)
contains supplementary material, which is available to authorized users.
&
Appaswami Lalitha
lalitha2531@yahoo.co.in
1
2
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, Periyar
University, Periyar Palkalai Nagar, Salem, Tamil Nadu 636011, India
Department of Chemistry, Salem Sowdeswari College, Salem, Tamil Nadu 636010, India
123

R. Ramesh et al.
Keywords Glycerol Á Catalyst-free Á Bis(3-methyl-1H-pyrazol-5-ol) Á
2,3-Dihydroquinazolin-4(1H)-one Á Green synthesis
Introduction
The exploration of proficient and environmentally benevolent routes for the
preparation of medicinally privileged organic molecules is a central goal of
synthesis research. Generally, nitrogen containing heterocycles are omnipresent in
several natural and biologically active synthetic molecules [1–3], and they have
emerged as core components in drug development because N-rich heterocyclic
compounds often improve dissolution and can facilitate salt formation [4]. Among
the variety of nitrogen heterocyclics, pyrazole and quinazolinone compounds have
received considerable interest, as they are present in natural as well as synthetic
pharmacologically potent molecules [5–7]. Considering the many properties of
glycerol, such as a long liquid range, unique solubility for polar organic compounds,
non-flammability and direct usage as a solvent, it would fit perfectly the
requirements of a green solvent [8]. Due to their unique behaviours, numerous
glycerol mediated organic transformations have been reported to be successful for
the synthesis of diverse heterocycles, such as hexahydro-9-aryl-xanthene-1,8-dione
[8], tetrahydrobenzo-4H-pyran [9], benzimidazole [10], 2-arylbenzothiazole [11],
triazolo[1,2-a]indazole-trione [12], 1H-tetrazole [13], 4,5-dihydropyrazoline [14]
and triarylimidazole [15].
The 4,40-(arylmethylene)bis(1H-pyrazol-5-ols) have attracted interest because
they exhibit a wide range of approved biological activities, being used as anticancer
[16], antipyretic [17], antidepressant [18], antiviral [19], antifungal [20], antitumor
[21], anti-inflammatory agents [22] and inhibitors of mycobacterium tuberculosis
[23]. Moreover, these compounds have been used as fungicides [24], pesticides and
dyestuffs [25, 26] and also have been employed as the chelating and extracting
reagents for different metal ions [27]. Some of the pyrazolone derivatives are
applied in many commercialized drugs for brain ischemia [28] and myocardial
ischemia [29]. Furthermore, a number of pyrazoles are used as intermediates in
organic synthesis [30] and as bis-Schiff bases in complex chemistry [31].
Similarly, 2,3-dihydroquinazolin-4(1H)-ones are also being offered as effective
antitumor [32, 33], anticancer [34], antidefibrillatory [35], antidepressant [36],
analgesic [37], diuretic [38], antihistamine [39], vasodilating [40], anticonvulsant
[41], antihypertensive [42], CNS stimulant [43], tranquilizer [44], antianxietic [45],
antiparkinsonism [46] and bronchodilator agents [47] and, very interestingly, they
have some plant growth regulating abilities [48]. Moreover, these compounds are
also used as valuable synthons for the preparation of pharmacologically potent
4(3H)-quinazolinone motifs by oxidation [49].
Due to the broad spectrum of applications, numerous synthetic routes have been
reported for the preparation of functionalized bis-3-methyl-1H-pyrazol-5-ol and 2,3-
dihydroquinazolin-4(1H)-one compounds. However, inspite of their efficiencies,
many of them suffer from limitations, such as use of expensive catalysts, prolonged
reaction times, low yields and tedious operational procedures. Therefore, finding an
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Glycerol assisted eco-friendly strategy for the facile…
efficient, high yielding and greener methodology for the synthesis of these
derivatives has attracted a great deal of attention. In continuation of our current
research devoted to the development of greener routes for the synthesis of
heterocyclic compounds [50–54], we wish to report herein the synthesis of potent
N-rich molecules in glycerol as an effective reaction medium. To the best of our
knowledge, this is the first report dealing with the glycerol assisted preparation of
4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) and 2-aryl-2,3-dihydroquina-
zolin-4(1H)-ones at benign conditions without the aid of any other catalysts.
Experimental
Reagents and equipments
A variety of substituted aromatic aldehydes, ethyl acetoacetate, hydrazine hydrate,
anthranilamide, cyclic ketones and solvents were purchased from commercial
sources (Sigma-Aldrich) and were used as received. Reactions were monitored by
TLC using silica gel 60 F254 aluminium sheets with ethyl acetate/hexanes as the
eluting medium. Melting points were determined with an electrothermal apparatus
by the open capillary method and are uncorrected. IR spectra were recorded on a
Bruker FT-IR27 spectrophotometer using KBr optics. NMR spectra were recorded
on a BRUKER DRX-400 MHz spectrometer in DMSO-d6 and d values are
expressed in ppm using TMS as an internal standard.
Typical procedure for the synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-
pyrazol-5-ols)
In a 25 ml RB flask containing glycerol (1.0 ml), a mixture of ethyl acetoacetate
(4.0 mmol) and hydrazine hydrate (4.0 mmol) was added and stirred at room
temperature for about 2 min. To the solid obtained, aromatic aldehyde (2.0 mmol)
was added and then the resulting mixture was stirred at 80 °C for the time specified
in Table 3. After completion of the reaction (as evidenced by TLC), the solid
obtained was treated with de-ionized water, well-stirred for a few minutes and
filtered. The solid product was washed with water and then recrystallized from
ethanol to afford a corresponding 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-
ols) in excellent purity for spectroscopic measurements. The glycerol present in the
filtrate was extracted with diethyl ether (2 9 5 ml) to remove any organic
compounds dissolved in the aqueous phase. The combined aqueous layer was
evaporated under reduced pressure at 100 °C to afford a pure glycerol which was
successfully reused for the next run with negligible loss in the product yields under
similar reaction conditions.
Spectral data for selected compounds
4,40-((4-Chlorophenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) (4b) White solid,
mp 210–212 °C; IR (KBr) (tmax/cm-1): 3670, 3515, 3435, 2753, 1602, 1489, 1090,
123

R. Ramesh et al.
852, 606; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.09 (s, 6H, 2CH3), 3.37 (2OH
exchanged with water of DMSO-d6), 4.83 (s, 1H, CH), 7.13 (d, 2H, ArH,
J = 8.0 Hz), 7.27 (d, 2H, ArH, J = 8.0 Hz), 11.33 (brs, 2H, 2NH); 13C NMR
(100 MHz, DMSO-d6): d (ppm) 10.3, 32.2, 103.8, 127.5, 129.3, 130.0, 139.6, 142.3,
160.9.
4,40-((4-Bromophenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) (4c) Light orange
solid, mp 216–218 °C; IR (KBr) (tmax/cm-1): 3742, 3105, 2945, 1600, 1530, 1209,
1004, 844, 604; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.07 (s, 6H, 2CH3), 3.41
(2OH exchanged with water of DMSO-d6), 4.79 (s, 1H, CH), 7.05 (d, 2H, ArH,
J = 8.0 Hz), 7.38 (d, 2H, ArH, J = 8.4 Hz), 11.33 (brs, 2H, 2NH); 13C NMR
(100 MHz, DMSO-d6): d (ppm) 10.3, 18.5, 32.2, 56.0, 103.7, 118.4, 129.7, 130.4,
131.9, 139.6, 142.7, 160.9.
4,40-((4-Nitrophenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) (4d) Yellow solid,
mp 272–274 °C; IR (KBr) (tmax/cm-1): 3691, 3559, 3309, 2967, 1612, 1511, 1381,
834, 612; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.08 (s, 6H, 2CH3), 3.39 (2OH
exchanged with water of DMSO-d6), 4.97 (s, 1H, CH), 7.36 (d, 2H, ArH,
J = 8.4 Hz), 8.10 (d, 2H, ArH, J = 8.0 Hz), 11.36 (brs, 2H, 2NH); 13C NMR
(100 MHz, DMSO-d6): d (ppm) 10.3, 32.6, 103.6, 127.3, 129.3, 130.2, 139.6, 142.7,
160.6.
4,40-((4-Hydroxyphenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) (4e) White solid,
mp 260–262 °C; IR (KBr) (tmax/cm-1): 3267, 2937, 2714, 1561, 1464, 1233, 1116,
845, 659; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.06 (s, 6H, 2CH3), 3.17 (2OH
exchanged with water of DMSO-d6), 3.68 (s, 3H, OCH3), 4.71 (s, 1H, CH), 6.58 (d,
2H, ArH, J = 8.4 Hz), 6.90 (d, 2H, ArH, J = 8.0 Hz), 9.06 (s, IH, OH), 11.3 (brs,
2H, 2NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 10.3, 31.9, 114.0, 114.4,
128.2, 133.4, 155.0.
4,40-(p-Tolylmethylene)bis(3-methyl-1H-pyrazol-5-ol) (4f) White solid, mp
192–194 °C; IR (KBr) (tmax/cm-1): 3563, 3297, 2919, 1607, 1513, 1380, 1213,
925, 834, 612; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.08 (s, 6H, 2CH3), 2.24 (s,
3H, CH3), 3.36 (2OH exchanged with water of DMSO-d6), 4.79 (s, 1H, CH), 7.02 (s,
4H, ArH), 10.7 (brs, 2H, 2NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 10.4,
20.5, 32.4, 48.6, 104.4, 127.4, 128.3, 134.2, 139.7, 140.2, 161.1.
4,40-((4-Methoxyphenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) (4g) Light orange
solid, mp 200–202 °C; IR (KBr) (tmax/cm-1): 3778, 2732, 1599, 1508, 1452, 1248,
1034, 840, 747, 604; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.06 (s, 6H, 2CH3),
3.43 (2OH exchanged with water of DMSO-d6), 3.68 (s, 3H, OCH3), 4.77 (s, 1H,
CH), 6.76 (d, 2H, ArH, J = 8.4 Hz), 7.02 (d, 2H, ArH, J = 8.4 Hz), 11.31 (brs, 2H,
2NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 10.3, 31.9, 54.9, 104.5, 113.1,
128.3, 135.2, 139.6, 157.1, 161.0.
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Glycerol assisted eco-friendly strategy for the facile…
Typical procedure for the synthesis of 2-aryl-2,3-dihydro-4(1H)-
quinazolinone derivatives
A mixture of aromatic aldehyde or cyclic ketone (2.0 mmol) and anthranilamide
(2.0 mmol) was added to a 25 ml RB flask containing 1.0 ml of glycerol. The
resulting mixture was stirred at 80 °C for the time specified in Tables 6 and 7. After
completion of the reaction (monitored by TLC), the reaction mixture was cooled to
room temperature and treated with de-ionized water (10 ml), well-stirred for a few
minutes, and the generated solid was filtered off. The crude products were
recrystallized from ethanol. The glycerol present in the filtrate was extracted with
diethyl ether (2 9 5 ml) to remove any organic compounds dissolved in the
aqueous phase. The combined aqueous layer was evaporated under reduced pressure
at 100 °C to afford a pure glycerol which was successfully reused for the next run
with negligible loss in the product yields under similar reaction conditions.
Spectral data for selected compounds
2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (6b) Colourless crystals;
mp 202–204 °C; IR (KBr) (tmax/cm-1): 3306, 3188, 3063, 2936, 1659, 1609,
1486, 1384, 1091; 1H NMR (400 MHz, DMSO-d6): d (ppm) 5.77 (s, 1H, CH), 6.66
(t, 2H, ArH, J = 7.6 Hz), 6.74 (d, 2H, ArH, J = 8.0 Hz), 7.14 (s, 1H, NH), 7.23 (d,
1H, ArH, J = 7.2 Hz), 7.44 (2d, 4H, ArH, J = 8.4 Hz), 7.60 (d, 1H, ArH,
J = 7.6 Hz), 8.33 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 65.7,
114.4, 114.9, 117.2, 127.3, 128.2, 128.7, 132.9, 133.3, 140.6, 147.6, 163.4.
2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (6d) Yellow crystals; mp
200–202 °C; IR (KBr) (tmax/cm-1): 3304, 3189, 3061, 2934, 1659, 1608, 1484,
1383, 1069; 1H NMR (400 MHz, DMSO-d6): d (ppm) 5.94 (s, 1H, CH), 6.67 (t, 1H,
ArH, J = 7.6 Hz), 6.78 (d, 1H, ArH, J = 8.0 Hz), 7.24 (t, 1H, ArH, J = 7.2 Hz),
7.33 (s, 1H, NH), 7.62 (d, 1H, ArH, J = 7.2 Hz), 7.75 (2d, 2H, ArH, J = 8.4 Hz),
8.24 (d, 2H, ArH, J = 8.8 Hz), 8.54 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d (ppm) 65.3, 114.5, 114.9, 117.4, 123.5, 127.4, 128.0, 133.5, 147.2, 147.4, 149.2,
163.3.
2-(4-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (6e) Colourless crystals;
mp 272–274 °C; IR (KBr) (tmax/cm-1): 3311, 3194, 3060, 2937, 1663, 1609,
1438, 1385, 1157; 1H NMR (400 MHz, DMSO-d6): d (ppm) 5.67 (s, 1H, CH), 6.66
(t, 1H, ArH, J = 7.2 Hz), 6.74 (m, 3H, ArH, J = 8.4 Hz), 6.95 (s, 1H, NH), 7.22 (t,
1H, ArH, J = 7.2 Hz), 7.31 (d, 2H, ArH, J = 8.8 Hz), 7.64 (d, 1H, ArH,
J = 8.0 Hz), 8.12 (s, 1H, NH), 9.52 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6):
d (ppm) 66.7, 114.4, 114.9, 117.0, 127.3, 128.3, 131.6, 133.2, 148.1, 157.7, 163.8.
2-(3,4-Dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (6i) Colourless crys-
tals; mp 212–214 °C; IR (KBr) (tmax/cm-1): 3309, 3195, 3065, 2939, 1668, 1611,
1
1437, 1386, 1099; H NMR (400 MHz, DMSO-d6): d (ppm) 3.34 (s, 3H, OCH3),
3.74 (s, 3H, OCH3), 5.69 (s, 1H, CH), 6.65–7.0 (m, 5H, ArH, J = 7.6 Hz), 7.12 (s,
1H, NH), 7.22 (t, 1H, ArH, J = 8.0 Hz), 7.60 (d, 1H, ArH, J = 7.6 Hz), 8.16 (s,
123

R. Ramesh et al.
1H, NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 55.2, 55.9, 66.4, 111.4, 114.6,
114.2, 115.4, 117.6, 119.3, 127.4, 132.5, 133.6, 147.2, 147.9, 148.6, 163.2.
2-(4-Hydroxy-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (6j) White solid;
mp 222–224 °C; IR (KBr) (tmax/cm-1): 3309, 3195, 3065, 2939, 1668, 1611, 1437,
1386, 1099; 1H NMR (400 MHz, DMSO-d6): d (ppm) 3.77 (s, 3H, OCH3), 5.66 (s,
1H, CH), 6.66–6.95 (m, 5H, ArH, J = 7.2 Hz), 7.10 (s, 1H, NH), 7.23 (t, 1H, ArH,
J = 7.2 Hz), 7.61 (d, 1H, ArH, J = 7.2 Hz), 8.11 (s, 1H, NH), 9.07 (s, 1H, OH);
13C NMR (100 MHz, DMSO-d6): d (ppm) 55.6, 66.8, 111.1, 114.4, 114.9, 115.0,
117.0, 119.6, 127.3, 131.9, 133.1, 146.9, 147.4, 148.1, 163.7.
10H-Spiro[cyclohexane-1,20-quinazolin]-4(30H)-one (8b) Colourless crystals; mp
220–222 °C; IR (KBr) (tmax/cm-1): 3364, 3269, 3173, 3029, 2929, 1644, 1487,
1380, 1093; 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23 (m, 2H, CH2), 1.61 (m,
8H, CH2) 6.60 (t, 1H, ArH), 6.63 (s, 1H, NH), 6.80 (d, 1H, ArH, J = 8.0 Hz), 7.18
(t, 1H, ArH, J = 6.8 Hz), 7.57 (d, 1H, ArH, J = 7.2 Hz), 7.95 (s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6): d (ppm) 20.8, 24.6, 37.1, 67.8, 114.4, 114.5, 116.4,
127.1, 133.1, 146.7, 163.2.
10H-Spiro[cyclopentane-1,20-quinazolin]-4(30H)-one (8c) Colourless crystals; mp
258–260 °C; IR (KBr) (tmax/cm-1): 3289, 3165, 3010, 2940, 1640, 1484, 1384,
1
1144; H NMR (400 MHz, DMSO-d6): d (ppm) 1.65 (m, 4H, CH2, J = 3.6 Hz),
1.77 (t, 4H, CH2, J = 5.2 Hz) 6.60 (t, 1H, ArH, J = 7.2 Hz), 6.68 (d, 1H, ArH,
J = 8.0 Hz), 6.73 (s, 1H, NH), 7.18 (t, 1H, ArH, J = 7.2 Hz), 7.56 (d, 1H, ArH,
J = 6.8 Hz), 8.09 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 21.9,
77.0, 114.3, 114.5, 116.5, 127.2, 132.9, 147.4, 163.4.
Results and discussion
To test our hypothesis, we began by examining the pseudo five-component reaction
of ethyl acetoacetate (1), hydrazine hydrate (2) and benzaldehyde (3a) as a model
for the synthesis of 4,40-(phenylmethylene)bis(3-methyl-1H-pyrazol-5-ol) (4a) in
neat conditions at room temperature. The reaction under neat conditions resulted in
the formation of 4a with a poor yield (27 %) even after 90 min.
Then, we studied the same reaction in different polar solvents such as ethanol,
methanol, acetonitrile and water, which also provided lower yields of product 4a,
whereas glycerol and PEG-400 on the model reaction resulted in much better yields
(59 and 51 % respectively) at ambient conditions. From the results outlined in
Table 1, we selected glycerol as an effective promoting medium due to the
increased yield in shorter reaction time for this multi-component reaction.
Next, to determine the optimal thermal conditions, we checked the above
reaction at different temperatures ranging from ambient to 100 °C. It was found that
80 °C would be a suitable temperature by providing 91 % of 4a in 3 min (Table 2).
However, further elevation in the temperature did not cause any significant
improvements in the yield of the product. Overall, this non-catalytic and
straightforward synthetic route turned out to be more efficient for the synthesis of
123

Glycerol assisted eco-friendly strategy for the facile…
Table 1 Optimization of suitable solvent
Entry
Solvent
Time (min)
Yieldb (%)
1
–
90
120
120
120
150
75
27
34
31
26
29
59
51
2
EtOH
3
MeOH
CH3CN
Water
Glycerol
PEG-400
4
5
6a
7a
75
Reaction conditions: ethyl acetoacetate (4.0 mmol), hydrazine hydrate (4.0 mmol) and benzaldehyde
(2.0 mmol) in different solvents (10 ml) stirred at room temperature
The suitable conditions for the synthesis of compound 4a was indicated by bold letters
a
Reaction conditions: ethyl acetoacetate (4.0 mmol), hydrazine hydrate (4.0 mmol) and benzaldehyde
(2.0 mmol) in solvent (1.0 ml) stirred at room temperature
b
Isolated yields
diverse 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) in a practical manner
(Scheme 1).
With these encouraging optimized results in hand, we investigated the generality
and effectiveness of this protocol with a variety of aromatic aldehydes 3(b–o).
Aldehydes bearing both electron-donating (methyl, methoxy or hydroxy) and
electron-withdrawing (nitro, chloro or bromo) substituents gave the corresponding
4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) in good yields within shorter
reaction times (Table 3). As can be seen from the same table, we can state that the
aldehydes containing ortho substituents also provided comparably good yields,
indicating that this method is not responsive to steric effects.
It is worth noting that the present green procedure was very simple and found to
be more efficient than conventional procedures (Table 4). After the reaction was
completed, the obtained residue was treated with water and was isolated by simple
filtration. All the synthesized compounds are known and were well characterized by
IR, 1H NMR and 13C NMR spectral analyses which were compared with the
literature. In the 1H NMR spectrum of compound 4b, a singlet appeared at d
11.33 ppm corresponding to the two NH protons in addition to a couple of doublets
at d 7.27 and 7.13 ppm for the aromatic protons. The benzylic methine (–CH)
proton appeared at d 4.83 ppm and also the two methyl (–CH3) protons appeared at
d 2.09 ppm as a singlet. The hydroxyl (–OH) protons are merged with the water of
DMSO-d6. In the 13C NMR, a signal at d 10.3 ppm indicates the presence of methyl
carbon and a peak at d 32.2 ppm denotes the existence of benzylic methine carbon
(–CH). Meanwhile, the IR spectrum shows two dissimilar bands at 3670 and
3435 cm-1 corresponding to –OH and –NH stretching.
A mechanism that tentatively accounts for the synthesis of 4(a–o) is shown in
Scheme 2. Initially, the condensation of ethyl acetoacetate (1) with hydrazine
hydrate (2) occurs to give the intermediate, 3-methyl-5-pyrazolone (II) which is
converted into III by tautomerisation. Then, III attacks the carbonyl carbon of the
123

R. Ramesh et al.
Yielda (%)
Table 2 Optimization of suitable temperature
Entry
Solvent
Temperature (°C)
Time (min)
1
2
3
4
5
6
7
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
RT
50
75
35
20
10
3
59
76
84
89
91
91
92
60
70
80
90
3
100
3
Reaction conditions: ethyl acetoacetate (4.0 mmol), hydrazine hydrate (4.0 mmol) and benzaldehyde
(2.0 mmol) in glycerol (1.0 ml) stirred at different temperature
The suitable conditions for the synthesis of compound 4a was indicated by bold letters
a
Isolated yields
R
H
O
O
.
H
2O
Glycerol
OEt
NH2
R
N
HN
N
NH
+
2 H N
+
80 oC
2
O
2
1-13 min
OH HO
4(a-o)
1
2
3(a-o)
Scheme 1 Glycerol assisted pseudo five-component synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-
pyrazol-5-ols)
aromatic aldehyde (3a) that is activated by the glycerol through the hydrogen
bonding and affords the intermediate IV, which on removal of a molecule of water
furnishes the Knoevenagel adduct V. Compound V acts as a Michael acceptor and is
activated by glycerol. In this step, another molecule of 3-methyl-5-pyrazolone II in
its tautomeric form (III) attacks the V to give intermediate VI. Finally, VI gets
converted to target product molecule (4a) by the tautomerisation step, which is
facilitated by the glycerol as an effective and greener solvent.
We were delighted by the non-catalytic results obtained in the above case and
wanted to further check the optimized protocol with another two-component system
through the reaction of benzaldehyde (3a) with anthranilamide (5) as starting
substrates. In this case, the expected 2-phenyl-2,3-dihydroquinazolin-4(1H)-one
(6a) was obtained in good yield (92 %) and the results were compared with that of
reported literature (Table 5). Next, we probed the generality of this methodology
with a variety of aromatic aldehydes 3(b-n) as shown in Scheme 3. Apparently, the
substituents in the aromatic ring do not affect the outcome significantly, furnishing
the desired 2-aryl-2,3-dihydroquinazolin-4(1H)-one derivatives 6(b-n) in much
shorter reaction times with excellent yields (Table 6). Similarly, the thiophene-2-
carboxaldehyde as hetero aryl aldehyde (3p) underwent cyclization very smoothly
with anthranilamide (5), which also provided the targeted 2-(thiophen-2-yl)-2,3-
dihydro-4(1H)-quinazoline (6p) in good yield (93 %, Table 6, Entry 15).
123

Glycerol assisted eco-friendly strategy for the facile…
Table 3 Non-catalytic approach for the synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols)
in glycerol
Entry
1
Aldehyde
Product
Time (min)
3
Yielda (%)
91
Mp (°C) [ref]
CHO
206–208 [57]
N
N
HN
NH
OH HO
Cl
CHO
Cl
2
3
4
5
6
7
8
3
2
94
91
94
88
90
89
90
210–212 [57]
216–218 [55]
272–274 [57]
260–262 [60]
192–194 [55]
200–202 [60]
262–264 [57]
N
HN
N
NH
HO
OH
CHO
Br
Br
N
HN
N
NH
OH
HO
CHO
NO2
NO2
1
N
HN
N
NH
OH HO
OH
CHO
OH
4
N
HN
N
NH
OH HO
CH3
CHO
CH3
2
N
HN
N
NH
OH
HO
CHO
OCH3
OCH3
1
N
HN
N
NH
OH
HO
CHO
Cl
Cl
13
Cl
Cl
N
N
HN
NH
OH HO
123

R. Ramesh et al.
Table 3 continued
Entry
9
Aldehyde
Product
Time (min)
10
Yielda (%)
86
Mp (°C) [ref]
CHO
OCH3
218–220
OCH3
OCH3
OCH3
CHO
N
HN
N
NH
OH HO
OH
10
3
85
240–242
OCH3
OCH3
OH
N
N
HN
NH
HO
HO
OH
OH
CHO
NO2
11
12
6
9
90
86
280–282 [57]
210–212 [57]
NO2
N
HN
N
NH
CHO
OH
OH
Cl
N
HN
N
NH
OH HO
OH HO
OH HO
OH HO
CHO
CHO
CHO
13
14
15
1
1
2
92
91
89
264–266 [57]
236–238 [60]
242–244 [60]
Cl
N
HN
N
NH
NO2
NO2
N
HN
N
NH
OH
OH
N
HN
N
NH
Reaction conditions: ethyl acetoacetate (4.0 mmol), hydrazine hydrate (4.0 mmol) and aromatic aldehyde
(2.0 mmol) in glycerol (1.0 ml) stirred at 80 °C
a
Isolated yields
Table 4 Comparison of efficiency of glycerol with some reported catalysts for the synthesis of 4a
Entry
Catalyst
Condition
Time (min)
Yield (%)
1
2
3
4
5
6
H3PW12O14
2-HEAP
EtOH/Reflux
15
20
23
60
10
3
91 [55]
Solvent-free, 90 °C
H2O/60 °C
H2O/Reflux
92 [56]
ZnAl2O4 NPs
SDS
87 [57]
87 [58]
HAP@AEPH2-SO3H
–
Solvent-free, 80 °C
Glycerol/80 °C
98 [59]
91 This work
123

Glycerol assisted eco-friendly strategy for the facile…
H
O
O
H
O
H
H
O
H
O
O
H
N
H
O
O
N
O
HN
O
OEt
HN
O
NH2
3a
H
H2N
O
H
O
H2N
O
H
N
-EtOH
-H2O
2
II
I
OEt
H
III
O
1
H
O
N
H
O
HN
O
H
H
-H2O
O
O
H
N
O
O
H
O
H
HO
N
O
IV
N
N
OEt
HN
O
HN
H2N
-
H2O
N
O
I
II
-EtOH
H
III
H
O
V
H
O
H
N
H
O
HO
O
N
N
HO
O
N
H
N
HN
N
NH
HN
N
HN
N
H
OH HO
4a
VI
Scheme 2 Plausible mechanistic approach in the formation of 4a
Table 5 Comparison of efficiency of glycerol with some reported catalysts for the synthesis of 6a
Entry
Catalyst
Condition
Time (min)
Yield (%)
1
Boehmite-SSA
Graphine oxide
Ce(MS)3
EtOH/Reflux
H2O/RT
50
20
20
10
35
10
8
96 [63]
94 [65]
93 [66]
96 [67]
89 [68]
98 [62]
94 [69]
94 [64]
93 [70]
91 [71]
93 This work
2
3
H2O/60 °C
CH3CN/RT
4
Cyanuric chloride
[Bmim]PF6
Co-CNT
5
Solvent-free, 75 °C
Solvent-free, MW
H2O/RT
6
7
H3PW12O40
p-SAC
8
H2O/RT
18
150
30
1
9
MES
Aq.EtOH/60 °C
EtOH/60 °C
Glycerol/80 °C
10
11
a-Chymotrypsin
–
H
O
O
O
NH
Glycerol
NH2
+
R
80 oC
N
H
NH2
1-4 min
R
3(a-n)
5
6(a-n)
Scheme 3 Glycerol assisted two-component synthesis of 2,3-dihydro-4(1H)-quinazolinones
123

R. Ramesh et al.
Table 6 Non-catalytic approach for synthesis of 2-aryl-2,3-dihydro-4(1H)-quinazolinones in glycerol
Entry
1
Aldehyde
Product
Time (min)
3
Yielda (%)
Mp (°C) [ref]
CHO
O
92
218–220 [61]
NH
N
H
CHO
O
2
1
4
3
1
2
2
1
3
1
93
95
91
89
90
90
92
89
87
202–204 [61]
194–196 [62]
200–202 [61]
272–274 [61]
228–230 [62]
186–188 [61]
168–170 [62]
212–214 [63]
222–224 [61]
NH
NH
NH
N
H
Cl
Cl
Br
CHO
O
3
N
H
Br
CHO
O
4
N
H
NO2
NO2
CHO
O
5
NH
NH
NH
N
H
OH
OH
CHO
O
6
N
H
CH3
CH3
CHO
O
7
N
H
OCH3
OCH3
CHO
Cl
O
8
NH Cl
N
H
Cl
Cl
CHO
O
9
NH
OCH3
OCH3
N
H
OCH3
OCH3
CHO
O
10
NH
OCH3
OH
OCH3
OH
N
H
CHO
O
11
12
3
3
93
91
184–186 [61]
204–206 [61]
NH
NO2
N
H
NO2
CHO
Cl
O
NH Cl
N
H
123

Glycerol assisted eco-friendly strategy for the facile…
Table 6 continued
Entry
13
Aldehyde
Product
Time (min)
1
Yielda (%)
90
Mp (°C) [ref]
CHO
NO2
O
190–192 [62]
NH NO2
N
H
CHO
OH
O
14
15
1
2
88
93
208–210 [61]
216–218 [64]
NH OH
N
H
CHO
S
O
NH
S
N
H
Reaction conditions: anthranilamide (2.0 mmol) and aromatic aldehyde (2.0 mmol) in glycerol (1.0 ml)
stirred at 80 °C
a
Isolated yields
H
H
O
H
O
O
O
O
O
O
O
H
H
O
H
O
H
O
H
O
H
H
N
NH2
O
H
N
H
H
N
O
N
N
H2N
H
H
+
-H2O
OH
H2N
3a
5
III
II
I
O
OH
HN
HN
N
H
6a
N
IV
Scheme 4 Plausible mechanistic approach in the formation of 6a
In the 1H NMR spectrum of compound 6b, the cyclic amide (–CONH) and amine
(–NH) protons appeared as singlets at d 8.33 and d 7.14 ppm respectively. The
benzylic methine (–CH) proton appeared at d 5.77 ppm as a singlet. The aromatic
protons appeared in the range of d 6.66–7.60 ppm. In 13C NMR spectrum, the cyclic
amide carbonyl carbon (–CONH) appeared at d 163.4 ppm. The benzylic carbon
(–CH) appeared at d 65.7 ppm and the aromatic carbon atoms appeared in the range
of d 114.4–147.6 ppm. The IR spectrum showed the bands at 3306 and 3188 cm-1
corresponding to the two NH stretchings. In addition to that, the NH bending
vibrations appeared at 1609 cm-1. Aromatic and aliphatic C–H stretching vibrations
appeared at 3063 and 2936 cm-1. A stretching corresponding to the carbonyl group
(–CO) appeared at 1659 cm-1
.
123

R. Ramesh et al.
O
O
O
NH
Glycerol
NH2
+
80 oC
N
H
1-3 min
NH2
5
7(a-c)
8(a-c)
Scheme 5 Glycerol assisted synthesis 1H-spiro-quinazolin-4-one derivatives
Table 7 Un-catalyzed synthesis of 1H-spiro-quinazolin-4-ones in glycerol
Entry
1
Ketone
Product
Time (min)
3
Yielda (%)
90
Mp (°C) [ref]
O
O
262–264 [72]
NH
O
N
H
N
H
NH
O
O
O
2
3
1
3
91
88
220–222 [72]
258–260 [72]
NH
N
H
O
O
NH
N
H
Reaction conditions: anthranilamide (2.0 mmol), cyclic ketone (2.0 mmol) in glycerol (1.0 ml) stirred at
80 °C
a
Isolated yields
A mechanism that accounts for the synthesis of 6(a–n) is shown in Scheme 4.
Initially, the glycerol might activate the carbonyl carbon of 3a, which would be
simultaneously attacked by the amino group of the anthranilamide (5) resulting in
the formation of hydroxyl intermediate I. Next, glycerol promotes the formation of
Schiff base (II) from I by the removal a water molecule. Finally, the imine
undergoes intramolecular cyclization through the tautomerization of ketoamide (II)
to enaminol (III) to furnish the corresponding product 6a in quantitative yields.
We also applied our protocol to the synthesis of some spiro-quinazolinones by
using various cyclic ketones 7(a–c) in place of aromatic aldehydes as represented in
Scheme 5. We were pleased to observe that the reaction of cyclic ketones with 5
under optimized thermal conditions furnished the desired 1H-spiro-1,2-quinazolin-
4(3H)-ones 8(a–c) in excellent yields in reasonably shorter times (Table 7).
Conclusion
We have established a glycerol mediated, benign, facile, mild and rapid protocol for
the efficient synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) and
2-aryl-2,3-dihydroquinazolin-4(1H)-one derivatives under catalyst-free conditions.
123

Glycerol assisted eco-friendly strategy for the facile…
The prominent merits of this route are the availability of starting materials, broad
substrate scope, much simpler work-up, economic viability and excellent yields of
desired products. This new chemistry is complementary to existing synthetic
procedures and suggests a powerful route for the progress of N-heterocyclic
scaffolds with more sensitive functionalities.
Acknowledgments R. R. gratefully acknowledge the DST-Inspire Fellowship, New Delhi, India (No:
DST/INSPIRE Fellowship/2012/690) for financial support.
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