Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

Article abstract of DOI:10.3762/BJOC.16.156

Natural dolomitic limestone (NDL) is employed as a heterogeneous green catalyst for the synthesis of medicinally valuable benzimidazoles, dihydropyrimidinones, and highly functionalized pyridines via C–N, C–C, and C–S bond formations in a mixture of ethan

Full text of DOI:10.3762/BJOC.16.156

Natural dolomitic limestone-catalyzed synthesis of
benzimidazoles, dihydropyrimidinones, and highly
substituted pyridines under ultrasound irradiation
Kumar Godugu‡1, Venkata Divya Sri Yadala‡1, Mohammad Khaja Mohinuddin Pinjari‡1,
Trivikram Reddy Gundala‡1, Lakshmi Reddy Sanapareddy2
and Chinna Gangi Reddy Nallagondu*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1881–1900.
1Department of Chemistry, Green and Sustainable Synthetic Organic
Chemistry Laboratory, Yogi Vemana University, Kadapa-516 005,
Andhra Pradesh, India and 2Department of Physics, S.V.D. College,
Kadapa-516003, Andhra Pradesh, India
doi:10.3762/bjoc.16.156
Received: 02 April 2020
Accepted: 23 July 2020
Published: 03 August 2020
Email:
Chinna Gangi Reddy Nallagondu* -
ncgreddy@yogivemanauniversity.ac.in
This article is part of the thematic issue "Green chemistry II".
Guest Editor: L. Vaccaro
* Corresponding author ‡ Equal contributors
© 2020 Godugu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
benzimidazoles; dihydropyrimidinones; highly substituted pyridines;
natural dolomitic limestone; ultrasound irradiation
Abstract
Natural dolomitic limestone (NDL) is employed as a heterogeneous green catalyst for the synthesis of medicinally valuable benzim-
idazoles, dihydropyrimidinones, and highly functionalized pyridines via C–N, C–C, and C–S bond formations in a mixture of
ethanol and H2O under ultrasound irradiation. The catalyst is characterized by XRD, FTIR, Raman spectroscopy, SEM, and EDAX
analysis. The main advantages of this methodology include the wide substrate scope, cleaner reaction profile, short reaction times,
and excellent isolated yields. The products do not require chromatographic purification, and the catalyst can be reused seven times.
Therefore, the catalyst is a greener alternative for the synthesis of the above N-heterocycles compared to the existing reported cata-
lysts.
Introduction
Nitrogen heterocycles are recognized as “privileged medicinal there is a great need for the development of a green and sustain-
scaffolds” because these compounds are found in a wide variety able synthetic route to the aforesaid nitrogen-containing hetero-
of bioactive natural products and pharmaceuticals [1-3]. Among cycles.
them, benzimidazoles, dihydropyrimidinones, and pyridines
have emerged as promising and valuable structural units in Benzimidazoles are an important class of N-heterocycles due to
many pharmaceutical lead compounds (Figure 1) [4-9]. Hence, their potential applications in both biology and medicinal chem-
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Figure 1: The benzimidazoles I–IV, dihydropyrimidinones/-thiones V–VIII, and 2-amino-4-aryl-3,5-dicarbonitrile-6-sulfanylpyridines IX–XII as medici-
nally privileged structures.
istry [10-13]. These compounds are used in the treatment of lysts for the Biginelli reaction [38-47]. In addition, some transi-
diseases, such as obesity, ischemia-reperfusion injury, hyperten- tion metal-based catalysts and a few nonacidic inorganic salts
sion, etc. [14-16]. In addition, these compounds are important are also utilized as catalysts for the above reaction [48-58].
intermediates in a variety of organic reactions and key elements Only few basic catalysts, such as t-BuOK, Ph3P, and ʟ-proline
in many functional materials [17-19]. Because of their potential are reported for the Biginelli reaction [59-61].
utility, a huge number of synthetic protocols has been de-
veloped for the preparation of benzimidazole derivatives. The 2-Amino-4-aryl-3,5-dicarbonitrile-6-sulfanylpyridines have
most common method for the preparation of benzimidazoles is gained considerable attention due to their wide-ranging biologi-
the reaction between o-phenylenediamines and carboxylic acids cal activities [62,63]. The most common synthetic route for the
[20,21]. Another general synthetic route reported is the conden- preparation of 2-amino-4-aryl-3,5-dicarbonitrile-6-thiopy-
sation reaction of o-phenylenediamine with aldehydes in the ridines is the condensation reaction of aldehydes, malononitrile,
presence of various catalysts, such as Zn–proline, trimethylsilyl and thiols in the presence of a variety of catalysts [64-72].
chloride (TMSCl), Amberlite® IR-120, indion 190, trifluoro- Though the reported methods are efficient to provide the
ethanol, YCl3, HClO4–SiO2, MMZY zeolite, Er(OTf)3, etc. [22- desired 1,2-disubstituted benzimidazoles, dihydropyrimidin-
30].
ones/-thiones and 2-amino-4-aryl-3,5-dicarbonitrile-6-
sulfanylpyridines, there are still some drawbacks, which include
Developments in already established multicomponent reactions the use of expensive catalysts, the preparation of the catalyst,
(MCRs) are interesting topics in organic synthesis. For instance, long reaction times, the limited substrate scope, and compli-
the Biginelli reaction is a renowned and tunable MCR to cated work-up processes; further, the products require chro-
synthesize the pharmacologically active 3,4-dihydropyrimidin- matographic purification.
2-(1H)-ones (DHPMs, Biginelli products) [31]. These com-
pounds occupy an important position in the fields of natural The mineral NDL is an irregular combination of calcium and
products and synthetic organic chemistry owing to their poten- magnesium carbonate. It is water-insoluble, environmentally
tial pharmacological properties [32-37]. A wide variety of benevolent, inexpensive, nontoxic, and abundant in nature.
Brønsted acids and Lewis acids are employed as efficient cata- Further, dolomite is used as a heterogeneous green catalyst in
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very few organic transformations, such as Knoevenagel, carbonate minerals, such as limestone and dolomite, are the
Michael–Henry, and transesterification reactions [73,74]. To the most abundant ones and common sedimentary rocks present in
best of our knowledge, there are no reports on the NDL-cata- this area.
lyzed synthesis of aforesaid N-heterocycles under ultrasonic ir-
radiation (USI).
Catalyst characterization
The NDL catalyst was ground into a fine powder and then
In this paper, we wish to report the use of NDL as a heterogen- sieved in a 200-mesh sieve. The chemical composition of the
eous green catalyst for the synthesis of the 1,2-disubstituted catalyst was determined by standard quantitative analysis. The
benzimidazoles 3, the dihydropyrimidinones/-thiones 7, and the basic strength of the catalyst was analyzed by using Hammett
2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6-sulfanylpyridines indicators. The catalyst was characterized by XRD, IR, Raman,
11 via C–N, C–C, and C–S bond-forming reactions, respective- SEM, and EDAX analysis.
ly, in a mixture of EtOH and H2O 1:1 under ultrasonic irradia-
tion (Scheme 1).
The chemical composition of the NDL was determined by
adopting a standard quantitative analysis [75]. The obtained
results are summarized in Table 1.
Results and Discussion
Geological background of the NDL catalyst
The NDL catalyst was collected from V. Kothapalli village The basic strength of the NDL catalyst (H_) was measured
(N 14°31’54”, E 78° 02’58”), Vemula Mandal of the Cuddapah using Hammett indicators, namely bromothymol blue
district, Rayalaseema, Andhra Pradesh, India. The rock forma- (H_ = 7.2), phenolphthalein (H_ = 9.8), 2,4-dinitroaniline
tion in the mineralized area of this village belongs to the (H_ = 15.0), and nitroaniline (H_ = 18.4) as Hammett indica-
Vempalli Formation (VF) of the Papaghni group of the lower tors. In each case, 5 mL of a methanolic solution of the
Cuddapah Supergroup in the Cuddapah Basin (CB). The Hammett indicator was added to 50 mg of the catalyst, shaken
Scheme 1: NDL-catalyzed synthesis of i) 1,2-disubstituted benzimidazoles 3, ii) dihydropyrimidinones/-thiones 7, and iii) 2-amino-4-(hetero)aryl-3,5-
dicarbonitrile-6-sulfanylpyridines 11 under ultrasound irradiation.
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Table 1: Chemical composition of the NDL catalyst. LOI: loss of ignition.
component
%
LOI
CaO
MgO
9.90
SiO2
7.3
Al2O3
0.94
Fe2O3
0.30
SO3
0.24
Na2O
0.28
K2O
0.05
38.90
41.84
well, and then allowed to equilibrate for 2 h. No color variation 5–586: calcite and 11–78: dolomite) [76,77]. Small quantities of
of the indicators was observed. The study revealed that the aluminium silicates (kaolinite) and iron oxides were also con-
basic strength of the NDL catalyst was weaker than the firmed by the XRD pattern. The less intense diffraction peaks at
bromothymol blue indicator, i.e., H_ < 7.2. Hence, the NDL 2θ = 12.3, 24.8, and 37.4 were assigned to the 001, 002, and
catalyst is a mild base, and it can activate both nucleophilic and 003 plane, respectively, of kaolinite (JCPDS card file 14-0164)
electrophilic groups [73]. Further, the amount of basic sites on [78]. The low-intense peaks at 2θ = 18.6, 26.1, 44.7, 54.6, 58.4,
the catalyst was estimated by titration using a standard benzoic and 63.0 were ascribed to the 111, 211, 400, 422, 511, and 440
acid solution and bromothymol blue indicator. Initially, the plane, respectively, of iron oxides (JCPDS card file 39-1346
catalyst (50 mg) was stirred with the methanolic solution of the and JCPDS card file 19-629) [79,80]. The above results were
indicator (5 mL) for 30–40 min, and then, the mixture was supported by FTIR and Raman characterization studies of the
titrated with a 0.02 M benzoic acid solution. From the titer catalyst (vide infra).
values of the benzoic acid solution, the amount of the basic sites
was found to be 0.033 mmol/g.
The FTIR spectrum of the catalyst is shown in Figure 3. In the
IR spectrum, two distinct vibrational modes of the carbonates,
The powder XRD pattern of the NDL catalyst is shown in i.e., out-of-plane bending and in-plane bending, were observed
Figure 2. The diffraction peaks at 2θ = 23.16, 29.51, 31.05, at 875 cm−1 (ν2) and 720 cm−1 (ν4), respectively. The bands at
36.02, 38.07, 39.40, 43.0, 47.2, 47.5, 48.5, 56.6, 57.6, 60.9, and 1086 cm−1 and 1424 cm−1 were ascribed to a symmetric
64.8° were attributed to the (012), (104), (006), (015), (110), stretching vibration (ν1) and an asymmetric stretching vibration
(113), (021), (024), (018), (116), (211), (122), (214), and (030) (ν3) of the carbonate group, respectively. The combined bands
plane, respectively, of the NDL catalyst (JCPDS card file of the carbonate group, i.e., ν1 + ν4 and ν1 + ν3 were observed at
Figure 2: XRD pattern of the NDL catalyst.
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Figure 3: FTIR spectrum of the NDL catalyst.
1798 and 2524 cm−1, respectively [76,77,81]. The IR bands at cated the presence of magnetically ordered ferromagnetic or
3446 cm−1 (broad) and 1674 cm−1 (sharp) indicated the pres- antiferromagnetic iron oxides [86]. The observed Raman and
ence of stretching and bending vibrations of water [82]. The infrared vibrational bands of the NDL were in good agreement
impurities aluminium silicate and iron oxides in the NDL were with the reported values. The minor shift in the band positions
confirmed by IR spectroscopy. The peaks located at 446, 551, might be due to the presence of trace metal contents and impuri-
817, 952, 1247, and 1383 cm−1 were attributed to the Si–O ties.
bending, Fe–O stretching, Al–O–Si stretching, Si–OH bending,
Si–O stretching, and Al–O bending, respectively [83,84]. The morphology of the NDL catalyst was analyzed by scanning
Further, the sharp band at 3696 cm−1 indicated the presence of a electron microscopy (Figure 5). The SEM images revealed that
well-ordered kaolinite structure [76].
the morphology of the NDL catalyst consists of irregular shapes
and sizes with a random dispersion. Further, the elemental com-
The Raman spectrum of the NDL catalyst is shown in Figure 4. position of the NDL catalyst was determined by EDAX analy-
The band at 1092 cm−1 was attributed to the symmetric sis (Figure 6).
stretching vibration (ν1) of the carbonate group. The peaks at
714 and 1435 cm−1 were assigned to a symmetric bending (ν4) The catalytic activity of the NDL for the synthesis of the 1,2-
and an asymmetric stretching vibration (ν3) of carbonate. The disubstituted benzimidazoles 3, the dihydropyrimidinones/-
weak peak at 1750 cm−1 was due to the combined band ν1 + ν4. thiones 7, and the 2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6-
The bands at 152 and 278 cm−1 were ascribed to the external sulfanylpyridines 11 was investigated, along with other, com-
vibrations of the carbonate group [76,77]. The presence of alu- mercially available catalysts.
minium silicates and iron oxides present in the sample were
NDL-catalyzed synthesis of 1,2-disubtituted
confirmed by Raman spectroscopy. The bands at 418, 578, 753,
and 985 cm−1 were assigned to Al–O bending, Si–O rocking, benzimidazoles 3
Al–O stretching, and Si–OH stretching vibrations, respectively To check the catalytic activity of the NDL, initially,
[85]. Further, a very weak peak at 618 cm−1 was attributed to o-phenylenediamine (1) and benzaldehyde (2a) were chosen as
iron oxide, and a very broad peak at 1312 cm−1 (magnon) indi- model substrates to optimize the reaction conditions for the syn-
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Figure 4: Raman spectrum of the NDL catalyst.
Figure 5: SEM images of the NDL catalyst.
thesis of 1-benzyl-2-phenyl-1H-benzo[d]imidazole (3a). At pyridine, and DABCO in different solvents, such as water, ace-
first, a control experiment was conducted by using model sub- tone, iPrOH, EtOH, and EtOH/H2O 1:1 (Table 2, entries 2–8)
strates, 1 and 2a, in H2O in the absence of catalyst under ultra- under ultrasound irradiation at 45–50 °C. From this study, it
sound irradiation for 60 min at 45–50 °C. It was found that the was observed that the NDL (2.5 wt %) was the best option,
reaction did not proceed in the absence of a catalyst (Table 2, which gave the target compound 3a in a high yield (85%) in a
entry 1). To achieve the target compound 3a, the same reaction mixture of EtOH and H2O 1:1 under ultrasound irradiation for
was repeated by employing various catalysts (2.5 wt %), such as 30 min at 45–50 °C (Table 2, entry 5). The other catalysts,
Fe2O3, Al2O3, KF–alumina, dolomitic limestone, triethylamine, Fe2O3, Al2O3, KF–alumina, triethylamine, pyridine, and
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Figure 6: EDAX analysis of the NDL catalyst.
Table 2: Optimization of the reaction conditions.a
entry
catalyst
(2.5 wt %)
solvent
product
conventional methodb
USIc
t (min)
yieldd (%)
t (min)
yieldd (%)
1e
2
no catalyst
Fe2O3
H2O
3a
3a
180
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
–
60
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
–
H2O
10
–
15
–
acetone
iPrOH
10
15
20
20
–
20
20
25
20
–
EtOH
EtOH/H2O 1:1
H2O
3
4
5
Al2O3
3a
3a
3a
acetone
iPrOH
15
25
30
30
–
20
25
40
30
–
EtOH
EtOH/H2O 1:1
H2O
KF–alumina
acetone
iPrOH
25
40
50
55
–
30
35
40
65
–
EtOH
EtOH/H2O 1:1
H2O
NDL
acetone
iPrOH
35
60
70
45
75
85
EtOH
EtOH/H2O 1:1
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 2: Optimization of the reaction conditions.a (continued)
6
7
8
Et3N
H2O
3a
3a
3a
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
10
–
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
10
–
acetone
iPrOH
10
15
10
–
10
20
10
–
EtOH
EtOH/H2O 1:1
H2O
pyridine
DABCO
acetone
iPrOH
–
–
5
5
EtOH
10
5
10
5
EtOH/H2O 1:1
H2O
10
–
5
acetone
iPrOH
–
15
15
10
5
EtOH
15
10
EtOH/H2O 1:1
aReaction conditions: o-phenylenediamine (1, 1.0 mmol), benzaldehyde (2a, 2.0 mmol), catalyst (2.5 wt %), solvent (3.0 mL). bPerformed by stirring at
reflux (entries 2–8). cUSI method performed at 45–50 °C. dIsolated yield. eConventional method performed by stirring at 45–50 °C.
DABCO, provided a moderate to low yield of the product 3a ation method is better than the conventional method in giving
(Table 2, entries 2–4 and 6–8). The aforesaid reaction was per- the maximum yield of 3a.
formed under conventional stirring of the model substrates 1
and 2a in H2O in the absence of catalyst for 180 min at Next, the amount of catalyst was varied (using 2.5, 5.0, 7.5,
45–50 °C. It was observed that the reaction did not proceed in 10.0, and 12.5 wt %, respectively,) to improve the yield of 3a
the absence of a catalyst (Table 2, entry 1). Further, when the (Table 3). The study revealed that 5.0 wt % of the NDL was the
reaction temperature was raised from 45–50 °C to reflux, a very best option to get the highest yield of the product 3a (98%) in a
low yield (10%) of the product 3a was obtained after 120 min. short reaction time (10 min, Table 3, entry 3). It was also
Next, the reaction was repeated in the presence of different cata- noticed that the same yield was obtained with an increasing
lysts and solvents at reflux under conventional reaction condi- amount of the catalyst, i.e., 7.5, 10.0, and 12.5 wt % (Table 3,
tions as mentioned in Table 2. The study revealed that the NDL entries 4–6).
in a mixture of EtOH and H2O 1:1 afforded a moderate yield
(70%) of the product 3a (Table 2, entry 5), whereas the other In order to demonstrate the effect of the temperature on the
catalysts, in various solvents, provided lower yields under simi- course of the model reaction, the control experiment was per-
lar reaction conditions (Table 2, entries 2–4 and 6–8). From the formed at different temperature ranges (30–35, 35–40, 40–45,
above observations, it was concluded that the ultrasound irradi- and 45–50 °C) by using the model substrates 1 and 2a in the
Table 3: Effect of the catalyst loading.a
entry
NDL (wt %)
solvent
t (min)
product
yieldb (%)
1
2
3
4
5
6
2.5
EtOH/H2O 1:1
EtOH/H2O 1:1
EtOH/H2O 1:1
EtOH/H2O 1:1
EtOH/H2O 1:1
EtOH/H2O 1:1
30
10
10
10
10
10
3a
3a
3a
3a
3a
3a
85
75
98
98
98
98
2.5
5.0
7.5
10.0
12.5
aReaction conditions: o-phenylenediamine (1, 1.0 mmol), benzaldehyde (2a, 2.0 mmol), NDL (2.5 to 12.5 wt %), EtOH/H2O 1:1 (3.0 mL), ultrasound
irradiation at 45–50 °C. bIsolated yield.
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
presence of 5.0 wt % of the NDL in a mixture of ethanol and ylylidene))diphenol (3h, bisimine I) within 10 min (Table 5,
water 1:1 for 10 min under both conventional stirring and ultra- entry 8). The reaction was expected to proceed through the acti-
sound irradiation. The obtained results are presented in Table 4. vation of the carbonyl group of 2h (of which 2.0 mmol were
It was observed that the reaction proceeded with an improved used) by the cations (Ca2+ and Mg2+, respectively) of the NDL.
yield of 3a (70–98%) by increasing the temperature range from This was followed by a nucleophilic attack of the NH2 groups
30–35 to 45–50 °C with an ultrasound irradiation method of o-phenylenediamine (1, of which 1.0 mmol was used), which
(Table 4, entries 1–4). Under conventional stirring, the yield of are activated by the carbonate part of the NDL, followed by
the product 3a increased from low to moderate when the reac- dehydration to obtain 3h (Scheme 2). Due to the mild basic
tion temperature was raised from 30–35 °C to reflux (Table 4, nature of the NDL catalyst, it acts as a dual activator of the elec-
entries 1–5). From the results, it was concluded that a tempera- trophilic carbonyl and the nucleophilic NH2 groups. The forma-
ture of 45–50 °C is the optimum temperature to obtain the tion of the bisimine I was confirmed by 1H NMR spectral
maximum yield of the desired product 3a within a short reac- studies (Figure 7). In the 1H NMR spectrum (DMSO-d6), the
tion time (10 min) under ultrasound irradiation (Table 4, entry two hydroxy protons of the bisimine I appeared as a broad,
4).
strongly downfield-shifted singlet at δ 13.19. The sharp singlet
at δ 8.66 indicated the two imine protons (–N=CH) of the
To demonstrate the generality and substrate scope of the present bisimine I. From this result, it was confirmed that the reaction
method, a variety of (hetero)aromatic aldehydes was investigat- stopped at the bisimine I stage. This was due to the intramolecu-
ed. The obtained results are presented in Table 5. o-Phenylene- lar hydrogen bonding between the hydrogen atom of the ortho-
diamine (1) reacted well with benzaldehyde (2a) to obtain the hydroxy group and the nitrogen atom of the imine group in a
corresponding product 3a with 98% yield (Table 5, entry 1). six-membered ring transition state [87]. Similarly, the reaction
The reactions of o-phenylenediamine (1) with substituted between 3-ethoxysalicylaldehyde (2i) and o-phenylenediamine
benzaldehydes having activating groups (4-Me: 2b, 4-t-Bu: 2c, (1) also ended with the intermediate 6,6'-((1E,1'E)-(1,2-
2,4-dimethyl: 2d, 4-OMe: 2e, 3,4-dimethoxy: 2f, 3,4,5- phenylenebis(azanylylidene))bis(methanylylidene))bis(2-
trimethoxy: 2g, 4-OH-3-OMe: 2j, and 4-OH-3-OC2H5: 2k, ethoxyphenol) (3i) stage (Table 4, entry 9 and Supporting Infor-
Table 5, entries 2–7, 10 and 11), a deactivating group (4-NO2: mation File 1, Figure S13). Most of the synthesized compounds
2l, Table 5, entry 12), or a halo group (4-F: 2m, 4-Cl: 2n, and are known and were identified easily by comparison of the
4-Br: 2o, Table 5, entries 13–15) in different positions provided melting point and spectroscopic data with those reported.
good to excellent isolated yields of the corresponding products
NDL-catalyzed synthesis of dihydropyrimidin-
3b–g and 3j–o that ranged from 94 to 98% in a stipulated period
of time, as specified in Table 5. Further, heteroaromatic alde- ones/-thiones 7
hydes, such as furan-2-aldehyde (2p) and thiophene-2-aldehyde The results encouraged us to further investigate the catalytic ac-
(2q) produced the corresponding products 3p and 3q in good tivity of the NDL in the Biginelli reaction. To check the feasi-
isolated yields within a short period of time (15 min and bility, a control experiment was performed by using the model
13 min, respectively, Table 5, entries 16 and 17).
substrates benzaldehyde (2a, 1.0 mmol), ethyl acetoacetate (4,
1.0 mmol), and urea (5, 1.0 mmol) in H2O (3.0 mL) in the
However, salicylaldehyde (2h) afforded the unexpected prod- absence of a catalyst under ultrasound irradiation at 45–50 °C
uct 2,2'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis(methan- for 60 min. It was observed that the reaction proceeded with a
Table 4: Effect of the temperature.a
entry
T (°C)
product
t (min)
conventional methodb
yieldd (%)
USIc
yieldd (%)
1
30–35
35–40
40–45
45–50
reflux
3a
3a
3a
3a
3a
10
10
70
79
87
98
–
2
10
14
3
10
20
4
10
26
5e
10/60
35/70
aReaction conditions: o-phenylenediamine (1, 1.0 mmol), benzaldehyde (2a, 2.0 mmol), NDL (5.0 wt %), EtOH/H2O 1:1 (3.0 mL). bConventional stir-
ring and heating with a silicone oil bath. cUltrasound irradiation in a water bath. dIsolated yield. eConventional stirring at reflux.
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 5: NDL-catalyzed synthesis of 2-aryl-1-arylmethyl-1H-benzo[d]imidazoles 3.a
entry
Ar
product
t (min)
yieldc (%)
mp (°C)
found
reported
1
phenyl: 2a
3a
3b
3c
3d
3e
3f
10
10
15
12
11
12
15
10
12
12
10
10
10
10
12
15
13
98
98
94
96
98
95
94
98
96
96
97
98
98
98
96
95
96
128–131
127–128
124–125
120–122
157–159
167–169
261–262
167–168
285–287
181–183
205–207
190–192
108–109
138–140
158–160
90–92
133–134 [23]
128–129 [23]
122–126 [25]
119–123 [25]
158–160 [23]
171–173 [24]
262–263 [22]
160–162 [23]
–
2
4-methylphenyl: 2b
4-tert-butylphenyl: 2c
2,4-dimethylphenyl: 2d
4-methoxyphenyl: 2e
3,4-dimethoxyphenyl: 2f
3,4,5-trimethoxyphenyl: 2g
2-hydroxyphenyl: 2h
2-hydroxy-3-ethoxyphenyl: 2i
4-hydroxy-3-methoxyphenyl: 2j
4-hydroxy-3-ethoxyphenyl: 2k
4-nitrophenyl: 2l
3
4
5
6
7
3g
3h
3i
8b
9b
10
11
12
13
14
15
16
17
3j
184–186 [24]
200–201 [26]
189–191 [23]
110–112 [23]
137–139 [23]
160–162 [23]
88–89 [23]
3k
3l
4-fluorophenyl: 2m
3m
3n
3o
3p
3q
4-chlorophenyl: 2n
4-bromophenyl: 2o
2-furanyl: 2p
2-thienyl: 2q
149–150
150–152 [23]
aReaction conditions: o-phenylenediamine (1, 1.0 mmol), aldehyde (2, 2.0 mmol), NDL (5.0 wt %), EtOH/H2O 1:1 (3.0 mL), USI, 45–50 °C. bThe
reaction stopped at the bisimine I, i.e., 3h/i stage. cIsolated yield.
Scheme 2: Unexpected formation of the bisimine I, 3h, from o-phenylenediamine (1) and salicylaldehyde (2h).
1890

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Figure 7: 1H NMR spectrum of 2,2'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis (methanylylidene))diphenol (bisimine I, 3h).
very low yield (20%) of product 7a. The same reaction was corresponding products (7h–j) in good isolated yields that
repeated in the presence of the NDL catalyst (5.0 wt %) in ranged from 93–96% (Table 6, entries 8–10). Heteroaromatic
EtOH/H2O 1:1 under ultrasound irradiation at 45–50 °C for aldehydes, such as furan-2-aldehyde (2p) and thiophene-2-alde-
15 min, which resulted in 97 % yield of 7a.
hyde (2q) showed a good reactivity, with good yields of 7k
(90%) and 7l (92%), respectively (Table 6, entries 11 and 12).
To exploit the substrate scope and generality of the method, From this study, it was concluded that the optimized reaction
various (hetero)aromatic aldehydes 2 were examined. The ob- conditions are suitable for monosubstituted (both electron-rich
tained results are summarized in Table 6. Benzaldehyde (2a) and electron-deficient) and disubstituted benzaldehyde deriva-
underwent the reaction with ethyl acetoacetate (4) and urea (5) tives as well as heteroaromatic aldehydes. To expand the scope
to obtain the corresponding dihydropyrimidinone 7a in of this method, thiourea (6) was also investigated (Table 6,
97% yield (Table 6, entry 1). Benzaldehyde derivatives entries 13–17). Benzaldehyde (2a) reacted with ethyl aceto-
bearing electron-donating groups, such as 4-Me (2b), 4-OMe acetate (4) and thiourea (6) to give the product 7m in an excel-
(2e), 3,4-dimethoxy (2f), 3-OH (2r), and 2-OH (2h), respective- lent isolated yield (96%, Table 6, entry 13). Benzaldehyde de-
ly, at different positions on the ring reacted well with ethyl rivatives bearing electron-donating groups, such as 4-Me (2b)
acetoacetate (4) and urea (5) to produce the products, 7b–f in and 4-OMe (2c) exhibited a good reactivity with ethyl aceto-
good isolated yields that ranged from 92–96% (Table 6, entries acetate (4) and thiourea (6) to produce the products 7n (95%)
2–6). A benzaldehyde derivative with an electron-accepting and 7o (95%) in excellent yields, respectively (Table 6, entries
nitro group (2l) at the para position on the ring showed a good 14 and 15). Benzaldehyde with electron-withdrawing groups,
reactivity with ethyl acetoacetate (4) and urea (5) to afford the such as 4-NO2 (2f) and 4-Cl (2i) at the para position reacted
product 7g in an excellent isolated yield (94%, Table 6, entry well with ethyl acetoacetate (4) and thiourea (6) to afford the
7). Halogen atoms at different positions on the ring of benzalde- corresponding products 7p and 7q in good isolated yields (94
hyde derivatives (4-F: 2m, 4-Cl; 2n, and 3-Br: 2s) underwent and 95%) (Table 6, entries 16 and 17). Most of the synthesized
the reaction with ethyl acetoacetate (4) and urea (5) to form the compounds are known and were identified easily by compari-
1891

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 6: NDL-catalyzed synthesis of dihydropyrimidinone/-thione derivatives 7.a
entry
Ar
X
product
t (min)
yieldb (%)
mp (°C)
found
reported
1
phenyl: 2a
O
O
O
O
O
O
O
O
O
O
O
O
S
7a
7b
7c
7d
7e
7f
15
15
17
18
17
15
12
13
12
18
20
20
15
15
17
10
11
97
96
96
94
95
92
94
95
96
93
90
92
96
95
95
94
95
207–209
213–214
200–201
213–215
162–164
198–200
210–211
176–179
208–210
184–185
204–206
216–218
211–212
189–190
148–150
113–114
190–191
209–210 [50]
215–216 [38]
199–202 [48]
212–214 [52]
163–165 [38]
199–201 [49]
209–212 [48]
175–177 [37]
209–211 [48]
185–186 [47]
203–205 [48]
215–217 [38]
208–210 [38]
192–194 [38]
150–152 [38]
109–111 [38]
192–194 [38]
2
4-methylphenyl: 2b
4-methoxyphenyl: 2e
3,4-dimethoxyphenyl: 2f
3-hydroxyphenyl: 2r
2-hydroxyphenyl: 2h
4-nitrophenyl: 2l
4-fluorophenyl: 2m
4-chlorophenyl: 2n
3-bromophenyl: 2s
2-furanyl: 2p
3
4
5
6
7
7g
7h
7i
8
9
10
11
12
13
14
15
16
17
7j
7k
7l
2-thienyl: 2q
phenyl: 2a
7m
7n
7o
7p
7q
4-methylphenyl: 2b
4-methoxyphenyl: 2e
4-nitrophenyl: 2l
4-chlorophenyl: 2n
S
S
S
S
aReaction conditions: aldehyde (2, 1.0 mmol), ethyl acetoacetate (4, 1.0 mmol), urea/thiourea (5/6, 1.0 mmol), NDL (5.0 wt %), ethanol/H2O 1:1
(3.0 mL), USI at 45–50 °C. bIsolated yield.
son of the melting point and spectroscopic data with those re- under ultrasound irradiation for 10 min, which resulted in 70%
ported.
yield of 11a. To improve the yield of 11a, the same reaction
was repeated at different time intervals; 15, 20, 25, 30, 35, and
40 min, respectively, at 45–50 °C, and the yields of 11a ob-
tained were 75, 83, 89, 96%, 96, and 96%, respectively. From
this study, it was found that the maximum yield of 11a (96%)
NDL-catalyzed synthesis of 2-amino-4-
(hetero)aryl-3,5-dicarbonitrile-6-
sulfanylpyridines 11
We further examined the catalytic efficacy of the NDL catalyst was obtained in 30 min, and the yields remained the same when
in the synthesis of the medicinally privileged highly functionali- the reaction time was increased from 30 to 40 min.
zed pyridines 11. For this purpose, a control experiment in the
absence of a catalyst was conducted by using the model sub- The optimized procedure was successfully applied for the syn-
strates benzaldehyde (2a, 1.0 mmol), malononitrile (8, thesis of a series of highly substituted pyridines (11b–r,
2.0 mmol), and 2-mercaptopyridine (9, 1.0 mmol) in H2O Table 7) by utilizing a range of (hetero)aromatic aldehydes 2,
(3.0 mL) under ultrasound irradiation at 45–50 °C for 60 min. It malononitrile (8), and the thiols 9 and 10, respectively, as
was observed that the reaction did not afford any product in the starting materials. Benzaldehyde (2a) underwent the reaction
absence of a catalyst. The above reaction was carried out in the with malononitrile (8) and 2-mercaptopyridine (9) to form prod-
presence of the NDL (5.0 wt %) in EtOH/H2O 1:1 (3.0 mL) uct 11a in 96% yield (Table 7, entry 1). Benzaldehyde deriva-
1892

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 7: NDL-catalyzed synthesis of 2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6-sulfanylpyridines 11.a
entry
Ar
R
product
t (min)
yieldb (%)
mp (°C)
found
reported
1
phenyl: 2a
pyridyl 9
11a
11b
11c
11d
11e
11f
30
35
40
35
32
32
30
37
45
30
30
35
38
30
30
30
34
42
96
96
92
94
96
95
94
90
93
98
98
97
94
95
96
96
94
94
222–223
248–249
267–269
223–224
241–243
248–250
257–258
252–253
230–231
210–212
206–207
234–235
240–241
280–282
127–128
220–221
250–253
300–302
224–227 [70]
250–253 [70]
265–268 [70]
222–226 [70]
245–248 [70]
246–249 [70]
260–263 [70]
251–254 [70]
233–235 [70]
215–216 [63]
208–210 [69]
236–238 [64]
238–239 [63]
286–287 [63]
224–225 [69]
222–223 [69]
256–258 [65]
305–306 [63]
2
4-methoxyphenyl: 2e
3,4,5-trimethoxyphenyl: 2g
3-hydroxyphenyl: 2r
4-nitrophenyl: 2l
pyridyl 9
3
pyridyl 9
4
pyridyl 9
5
pyridyl 9
6
4-fluorophenyl: 2m
4-bromophenyl: 2o
3,4-difluorophenyl: 2t
pyridyl: 2u
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
7
11g
11h
11i
8
9
10
11
12
13
14
15
16
17
18
phenyl: 2a
11j
4-methylphenyl: 2b
4-methoxyphenyl: 2e
3,4,5-trimethoxyphenyl: 2g
4-nitrophenyl: 2l
11k
11l
11m
11n
11o
11p
11q
11r
4-fluorophenyl: 2m
4-chlorophenyl: 2n
3-bromophenyl: 2s
pyridyl: 2u
aReaction conditions: aldehyde (2, 1.0 mmol), malononitrile (8, 2.0 mmol), thiol 9 or 10 (1.0 mmol), NDL (5.0 wt %), EtOH/H2O 1:1 (3.0 mL), USI at
45–50 °C. bIsolated yield.
tives containing a range of functional groups, such as electron- yields, ranging from 94 to 98% (Table 7, entries 11–17). Pyri-
donating groups (4-OMe: 2e, 3,4,5-trimethoxy: 2g, and 3-OH: dine-2-aldehyde (2u) also provided the product 11r in a good
2r), an electron-withdrawing group (4-NO2: 2l), and halogen yield (94%, Table 7, entry 18). It was observed from the above
atoms (4-F: 2m, 4-Cl: 2n, and 3,4-difluoro: 2t), respectively, at results that all reactions proceeded well irrespective of the sub-
different positions on the aromatic ring showed a good reactivi- stituents present on the (hetero)aromatic aldehyde and afforded
ty with the said reactants and afforded the corresponding prod- the highly substituted pyridines 11 in good isolated yields that
ucts 11b–h that ranged from 90 to 96% (Table 7, entries 2–8). ranged from 90 to 98%. Most of the synthesized compounds are
Further, the use of pyridine-2-aldehyde (2u) resulted in a good known and were identified easily by comparison of the melting
isolated yield of 11i (93%, Table 7, entry 9). In a similar way, point and spectroscopic data with those reported.
the reaction of benzaldehyde (2a) with malononitrile (8) and
thiophenol (10) gave the product 11j in 98% yield (Table 7,
Evaluation of the green chemistry metrics for
entry 10). Benzaldehyde derivatives bearing various functional
the synthesis of benzimidazoles 3,
groups, such as electron-donating groups (4-Me: 2b, 4-OMe:
dihydropyrimidinones 7, and highly
2e, and 3,4,5-trimethoxy: 2g), an electron-accepting group
(4-NO2: 2l), and halogen atoms (4-F: 2m, 4-Cl: 2n, and 3-Br: functionalized pyridines 11
2s), respectively, at different positions on the aromatic ring In order to evaluate the “greenness” of the proposed methodolo-
displayed a good reactivity with malononitrile (8) and thio- gies, the green chemistry metrics, such as the atom economy
phenol (10) to give the corresponding products (11k–q) in good (AE), E-factor, process mass intensity (PMI), Curzon’s reac-
1893

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
tion mass efficiency (RME), and generalized or global reaction Catalyst reusability experiments
mass efficiency (gRME) were evaluated by adopting estab- Catalyst reusability tests were performed showcasing the syn-
lished standard empirical formulae [88,89]. The obtained results thesis of the compounds 3k, 7a, and 11e under the optimized
are summarized in Tables 8–10. This study revealed that the reaction conditions.
reactions displayed a good to excellent AE (88–95%) and
Curzon’s RME (78–93%) as well as a low to moderate E-factor Catalyst reusability experiments in the synthesis of
(26.202–50.760) and PMI (27.202–51.760). The detailed calcu- compounds 3k, 7a, and 11e
lations of the green chemistry metrics (AE, E-factor, PMI, The catalyst was tested for reusability in the preparation of 3k
Curzon’s RME, and gRME) for the synthesis of the compounds using o-phenylenediamine (1) and 3-ethoxy-4-hydroxybenz-
3a, 7a, and 11a (Table 8, entry 1, Table 9, entry 1, and aldehyde (2k) under USI for 10 min. After completion of the
Table 10, entry 1) are presented in Supporting Information first reaction cycle, the reaction mass was allowed to cool to rt,
File 1 (see Reaction-S1–Reaction-S3).
and ethyl acetate (4.0 mL) was added. Then, the catalyst was
Table 8: Green chemistry metrics for the synthesis of 2-aryl-1-arylmethyl-1H-benzo[d]imidazoles 3.
entry
Ar
product
AEa (%)
E-factorb
PMIc
Curzon’s
RMEd
(%)
gRMEe
(%)
1
phenyl: 2a
3a
3b
3c
3d
3e
3f
89
90
92
90
91
92
93
90
92
91
92
91
90
91
93
88
89
40.864
37.261
30.614
35.044
33.837
29.729
26.202
36.781
29.412
31.609
29.102
31.017
36.312
33.052
26.920
45.454
40.169
41.864
38.261
31.614
36.044
34.837
30.729
27.202
37.781
30.412
32.609
30.102
32.017
37.312
34.052
27.920
46.454
41.169
87
88
86
86
89
87
87
88
88
88
89
89
88
89
89
84
85
2.4
2.6
3.2
2.8
2.9
3.3
3.7
2.6
3.3
3.1
3.3
3.1
2.7
2.9
3.6
2.2
2.4
2
4-methylphenyl: 2b
3
4-tert-butylphenyl: 2c
2,4-dimethylphenyl: 2d
4-methoxyphenyl: 2e
3,4-dimethoxyphenyl: 2f
3,4,5-trimethoxyphenyl: 2g
2-hydroxyphenyl: 2h
2-hydroxy-3-ethoxyphenyl: 2i
4
5
6
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
4-hydroxy-3-methoxyphenyl: 2j 3j
4-hydroxy-3-ethoxyphenyl: 2k
4-nitrophenyl: 2l
3k
3l
4-fluorophenyl: 2m
4-chlorophenyl: 2n
4-bromophenyl: 2o
2-furanyl: 2p
3m
3n
3o
3p
3q
2-thienyl: 2q
aAE = 100⋅(GMW of the product/sum of the GMWs of the reactants); GMW = gram molecular weight. bE-factor = total input mass (minputs)f − mass of
the target product (m3) − mass of the recovered materials/m3. cPMI = (minputs − mass of the recovered materials)/m3 or 1 + E-factor.
dCurzon’s RME = m3/ m1 + m2 or yield × AE × 1/stoichiometric factor (SF); SF = 1. egRME = 100⋅(m3/(minputs − mass of the recovered materials)) or
100⋅(1/(1 + E-factor)). fTotal input mass, including water (minputs) = m1 + m2 + msolvent (S) + mcatalyst (C) + mwork-up materials (WPM) + mpurifica-
tion materials (PM).
1894

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 9: Green chemistry metrics for the synthesis of dihydropyrimidinones/-thiones 7.
entry
reactants
Ar
product
AE (%)
E-factora
PMIb
Curzon’s RMEc gRMEd
(%)
(%)
5/6
1
phenyl: 2a
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
7a
7b
7c
7d
7e
7f
88
88
89
90
89
89
89
89
89
90
87
88
89
89
90
90
90
45.254
43.373
41.036
37.924
43.550
44.953
39.770
43.220
40.311
36.254
50.760
46.600
43.045
41.341
39.213
37.978
38.685
46.254
44.373
42.036
38.924
44.550
45.953
40.770
44.220
41.311
37.254
51.760
47.600
44.045
41.341
40.213
38.978
39.685
85
84
85
85
85
82
84
85
85
84
78
81
85
85
86
85
86
2.2
2.3
2.4
2.6
2.2
2.2
2.5
2.3
2.4
2.7
1.9
2.1
2.3
2.4
2.5
2.6
2.5
2
4-methylphenyl: 2b
4-methoxyphenyl: 2e
3,4-dimethoxyphenyl: 2f
3-hydroxyphenyl: 2r
2-hydroxyphenyl: 2h
4-nitrophenyl: 2l
4-fluorophenyl: 2m
4-chlorophenyl: 2n
3-bromophenyl: 2s
2-furanyl: 2p
3
4
5
6
7
7g
7h
7i
8
9
10
11
12
13
14
15
16
17
7j
7k
7l
2-thienyl: 2q
phenyl: 2a
7m
7n
7o
7p
7q
4-methylphenyl: 2b
4-methoxyphenyl: 2e
4-nitrophenyl: 2l
4-chlorophenyl: 2n
aE-factor = minputse − mass of the target product (m7) − mass of the recovered materials/m7. bPMI = (minputs − mass of the recovered materials)/m7
or 1 + E-factor. cCurzon’s RME = m7/m2 + m 4 + m5/6 or yield × AE × 1/SF; SF = 1. dgRME = 100⋅(m7/(minputs − mass of the recovered materials)) or
100⋅(1/(1 + E-factor)). eminputs = m2 + m4 + m5/6 + mS + mC + mWPM + mpurification materials (PM).
separated by vacuum filtration, washed with ethyl acetate noticed that the catalyst could successfully be reused (at least)
(1.0 mL), dried under vacuum, and reused in the next cycles. 7 times in the synthesis of the compounds 3k, 7a, and 11e with-
The study revealed that the obtained yields of the product, 3k out a significant loss of the catalytic activity.
were 98, 98, 97, 97, 96, 97, and 98% for the first, second, third,
fourth, fifth, sixth, and seventh cycle, respectively. Catalyst re- Effect of ultrasonication on the structure of the
usability tests were then conducted for the synthesis of com- catalyst
pound 7a using benzaldehyde (2a), ethyl acetoacetate (4), and The recovered catalyst after the 7th cycle of each synthesis was
urea (5) under USI for 15 min and for 11e using 4-nitroben- characterized by XRD to study the structural changes due to
zaldehyde (2l), malononitrile (8), and 2-mercaptopyridine (9) ultrasonication. As can be seen in Figure 8, the diffraction peak
under USI for 32 min by following the same procedure as positions of the catalyst recovered after the synthesis of the
adopted for 3k. The yields obtained for the compounds were 97, compounds 3k, 7a, and 11e (Figure 8b–d), respectively,
97, 97, 96, 97, 97, and 97% for 7a as well as 96, 96, 96, 97, 97, remained the same as compared to the fresh catalyst
97, and 98% for 11e for the first, second, third, fourth, fifth, (Figure 8a). It was also noticed that the broadening in the XRD
sixth, and seventh cycle, respectively. From this study, it was pattern of the recovered catalyst had increased with an increase
1895

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Table 10: Green chemistry metrics for the synthesis of 2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6-sulfanylpyridines 11.
entry reactants
Ar
product
AE (%)
E-factora
PMIb
Curzon’s
RMEc
(%)
gRMEd
(%)
R
1
phenyl: 2a
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
pyridyl: 9
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
phenyl: 10
11a
11b
11c
11d
11e
11f
94
95
95
95
95
95
95
95
94
94
95
95
95
95
95
95
95
94
36.054
33.026.
29.647
35.188
31.741
34.356
29.698
34.699
37.143
35.474
33.991
32.827
29.020
32.021
34.319
32.744
29.775
36.893
37.054
34.026
30.647
36.188
32.741
35.356
30.698
35.699
38.143
36.474
34.991
33.827
30.020
33.021
35.319
33.744
30.775
37.893
90
91
87
89
91
90
89
86
87
92
93
92
89
90
91
91
89
88
2.7
2.9
3.3
2.8
3.1
2.8
3.3
2.8
2.6
2.7
2.9
3.0
3.3
3.0
2.8
3.0
3.2
2.6
2
4-methoxyphenyl: 2e
3,4,5-trimethoxyphenyl: 2g
3-hydroxyphenyl: 2r
4-nitrophenyl: 2l
3
4
5
6
4-fluorophenyl: 2m
4-bromophenyl: 2o
3,4-difluorophenyl: 2t
pyridyl: 2u
7
11g
11h
11i
8
9
10
11
12
13
14
15
16
17
18
Phenyl: 2a
11j
4-methylphenyl: 2b
4-methoxyphenyl: 2e
3,4,5-trimethoxyphenyl: 2g
4-nitrophenyl: 2l
11k
11l
11m
11n
11o
11p
11q
11r
4-fluorophenyl: 2m
4-chlorophenyl: 2n
3-bromophenyl: 2s
pyridyl: 2u
aE-factor = minputsf − mass of the target product (m11) − mass of the recovered materials/m11. bPMI = (minputs − mass of the recovered materials)/
m11 or 1 + E-factor. cCurzon’s RME = m11/ m2 + m8 + m9/10 or yield × AE × 1/SF; SF = 1. dgRME = 100⋅(m11/(minputs − mass of the recovered mate-
rials)) or 100⋅(1/(1 + E-factor)). eminputs = m2 + m8 + m9/10 + mS + mC + mWPM + mPM.
of the ultrasonication time. This clearly indicated that the amor- yield. Besides, the products obtained were in an adequate purity
phization of the recovered catalyst was enhanced by increasing without the need for chromatographic separation, and the cata-
the ultrasonication time.
lyst was reused 7 times without a significant loss of the catalyt-
ic activity. Hence, the catalyst is a greener alternative for the
synthesis of 1,2-disubstituted benzimidazoles, dihydropyrimi-
Conclusion
An environmentally benign NDL catalyst was characterized and dinones/-thiones, and highly substituted pyridines when com-
utilized as a heterogeneous catalyst for the synthesis of 2-aryl- pared to the existing reported catalysts. Further, the expansion
1-arylmethyl-1H-benzo[d]imidazoles, dihydropyrimidinones/ of the catalyst scope and the generality for the synthesis of other
-thiones, and 2-amino-4-(hetero)aryl-3,5-dicarbonitrile-6- privileged nitrogen- and sulfur-based heterocycles is under
sulfanylpyridines in a mixture of ethanol and H2O 1:1 under progress in our laboratory.
ultrasound irradiation. Notable advantages of this methodology
include the clean reaction profile, broad substrate scope, Experimental
simplicity of the process and handling, low catalyst loading, and See Supporting Information File 1 for full experimental data of
the easy and quick isolation of the products in good to excellent compounds 3, 7, and 11.
1896

Beilstein J. Org. Chem. 2020, 16, 1881–1900.
Figure 8: XRD pattern of a) the fresh NDL catalyst; b) the recovered NDL catalyst after the 7th cycle of the ultrasonic synthesis of 3k; c) the recov-
ered NDL catalyst after the 7th cycle of the ultrasonic synthesis of 7a; and d) the recovered NDL catalyst after the 7th cycle of the ultrasonic synthe-
sis of 11e.
Acknowledgements
Supporting Information
The authors thank Dr. R. V. J. Kashyap, Dept. of English, Yogi
Vemana University, for critical reading of the manuscript to
ensure linguistic correctness.
Supporting Information File 1
Experimental procedures, characterization data, and copies
of the 1H and 13C NMR, mass, and HRMS spectra of 3, 7,
and 11.
Funding
The authors gratefully acknowledge the financial support for
this work from the Department of Atomic Energy Board of
Research in Nuclear Sciences (Bhabha Atomic Research
Centre), Mumbai, Government of India, through a major
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-156-S1.pdf]
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Beilstein J. Org. Chem. 2020, 16, 1881–1900.
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ORCID® iDs
Lakshmi Reddy Sanapareddy - https://orcid.org/0000-0001-9475-5516
Chinna Gangi Reddy Nallagondu - https://orcid.org/0000-0003-2088-802X
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