NH4Cl/Zn powder: An efficient, chemoselective reducing catalyst for the microwave-assisted synthesis of 2,3-disubstituted quinolines via tandem Knoevenagel condensation

Article abstract of DOI:10.1002/jhet.4203

An efficient, a hitherto unreported, sustainable, and environmentally friendly microwave-assisted synthesis of 2,3-disubstituted quinolines by reductive cyclization of 2-nitrobenzaldehydes and various active methylene compounds via tandem Knoevenagel condensation promoted by an efficient eco-friendly, chemoselective reducing catalyst ammonium chloride (NH₄Cl) and zinc powder was developed. This present methodology is a mild, green, efficient, and environmentally benign process as it eliminates the harsh reaction conditions, non-volatile solvents, relatively expensive reagents, high catalyst loading, and also provides a number of other benefits like fast synthesis, simple reaction set-up, and good to the excellent yield of the products.

Full text of DOI:10.1002/jhet.4203

NH4Cl/Zn powder: An efficient, chemoselective reducing catalyst for the
microwave-assisted synthesis of 2,3-disubstituted quinolines via tandem
Knoevenagel condensation
S. Tasqeeruddina*, Yahya I. Asirib, S. Shaheenc
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha,
Saudi Arabia
bDepartment of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi
Arabia
cAnwarul Uloom College of Pharmacy, Mallepally, Hyderabad, India
Email Id: drsyedtasqeeruddin@gmail.com
Abstract
An efficient, a hitherto unreported, sustainable, and environmentally friendly microwave-assisted
synthesis of 2,3-disubstituted quinolines by reductive cyclization of 2-nitrobenzaldehydes and
various active methylene compounds via tandem Knoevenagel condensation promoted by an
efficient eco-friendly, chemoselective reducing catalyst ammonium chloride (NH4Cl) and zinc
powder was developed. This present methodology is a mild, green, efficient, and
environmentally benign process as it eliminates the harsh reaction conditions, non-volatile
solvents, relatively expensive reagents, high catalyst loading, and also provides a number of
other benefits like fast synthesis, simple reaction set-up, and good to the excellent yield of the
products.
Key words
Microwave assisted synthesis; Knoevenagel condensation and reductive cyclization; NH4Cl/Zn a
chemoselective catalyst; quinoline derivatives
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INTRODUCTION
Quinoline moiety exists in numerous natural products, especially in alkaloids, and is often used
for the synthesis of many pharmacologically active compounds.[1] A number of quinoline
derivatives are pharmacologically important because of their wide spectrum of biological
activities.[2] Quinoline moieties have attracted both synthetic chemists and biologists as they are
crucial components of various naturally existing pharmacologically active compounds.[3]
Fig. 1. Chemical structures of pharmacologically active quinolone moieties
Some promising quinoline derivatives are shown in Figure 1. It was found that quinoline
moieties possess a wide range of pharmacological properties like antibacterial,[4] antifungal,[5]
anticancer,[6] antiviral,[7] and antimalarial.[8] Therefore, the construction of pharmacologically
active quinoline moieties has gained enough interest in synthetic organic chemists. Various
methods were established for designing the quinoline derivatives including the Skraup,[9]
Conrad-Limpach-Knorr,[10] Pfitzinger,[11] Friedlander,[12] and Friedlander condensation.[13-18]
2
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For the synthesis of quinoline moieties, different new strategies were set up which utilizes
metallic or organometallic chemicals such as CuCN, LiCl,[19] RuCl3.nH2O/3PPh3,[20]
Yb(OTf)3,[21] W(CO)5(THF),[22] BF3.OEt2,[23,24]
Benzotriazoleiminium salts,[25] etc.
Notwithstanding the numerous merits detailed by these strategies be that as it may be, they are
too tormented by impediments like destitute yields, troublesome work-up, and gushing
contamination.
These days, sustainable reactions are the challenge for chemists in zones like health,
social concern, environment and to beat these problems it’s aimed to develop straightforward and
simple strategies to conduct organic reactions under gentle conditions.[26] Reactions performed
under microwave oven offers various benefits such as short reaction time, good to the excellent
yield of the product, eco-friendly in nature, and consumes less heat (thermal energy).[27,28]
In the radiance of the above-mentioned facts, and as part of our continuing investigation
about committed to the improvement of a facile, simple, and commercially affordable methods
for the synthesis of various organic compounds,[29,30] an attempt has been through to carry out a
highly atom-economic synthesis of 2,3-disubstituted quinoline derivatives by reductive
cyclization of 2-nitrobenzaldehydes and various active methylene compounds via tandem
Knoevenagel condensation under microwave irradiation in NH4Cl and zinc powder. In the
literature, it has been reported that there is growing interest in ammonium chloride as a catalyst
due to its soft, most diligent activities, eco-friendly property, commercially accessible, and
affordable.[31] Very recently ammonium chloride is effectively used in the chemoselective
reduction of nitro compounds to aromatic amines with samarium metal,[32] reduction of azides to
amines or amides,[33] reductive cleavage of azo compounds to Amines.[34] Thus we planned to
develop a new method for synthesis of quinoline derivatives by using ammonium chloride as a
mild acid catalyst that can avoid the restriction of functionally substituted substrates.
RESULTS AND DISCUSSION
At the initial stage of reaction, we evaluated the most favorable requirements with respect
to the volume of solvent, the quantity of catalyst, reaction time, and watt power of microwave
radiations. For this cause, the reaction of 2-nitrobenzaldehyde (1) and ethyl cyanoacetate (2)
under microwave irradiation in the presence of NH4Cl/Zn powder catalyst was chosen as a model
3
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reaction (Scheme 1). When the reaction was conducted under solvent-free conditions in the
absence of a catalyst (Table 1, entry 1), only a 10% yield of the desired product (3a) was
observed. Next, we investigated the effect of solvents on the reaction rate and yield of the
product. It is to be noted here that, the yield of the product obtained under solvent-free condition
is higher than the yield of the product obtained with various solvents like EtOH, H2O, C6H5CH3,
CH3CN, and DMF (Table 1, entries 2,3,4,5,6).
Scheme 1: Synthesis of 2,3-disubstituted quinoline.
Table 1: Investigation of reaction conditions for the synthesis of quinoline derivativesa
Entry Solvent
NH4Cl/Zn-Catalyst (mole %) Temp (Watt) Time (min)
Yield (%)
1
-
-
400
400
400
400
400
400
200
300
400
400
400
400
400
400
10
10
10
10
10
10
10
10
4
10
80
60
60
60
50
50
80
98
60
70
85
98
95
2
EtOH
10
10
10
10
10
10
10
10
2.5
5
3
H2O
4
C6H5CH3
5
CH3CN
6
DMF
7
-
-
-
-
-
-
-
-
8
9
10
11
12
13
14
4
4
8
4
10
15
4
4
aReaction condition: 2-nitrobezaldehyde (10 mmol), ethyl cyanoacetate (10 mmol).
bYields of the isolated products.
4
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The most extreme power of the microwave radiation was optimized by conducting the
above model scheme at distinctive watt powers (200, 300, 400 W). Microwave radiations at 400
W and reaction time 4 min gave the highest yield of the desired product (Table 1, entries 7, 8, 9).
Next, we investigated the impact of the sum of catalyst the (NH4Cl/Zn). The optimized condition
shows that 1.5 mmol Zn powder (10 mol%) and 1 mmol NH4Cl (10 mol%) was sufficient to get
a maximum yield of the desired product. The optimum amount of catalyst (NH4Cl/Zn) required
in the above reaction was studied by changing the amount of catalyst from 2.5, 5, 8, 10, and 15
mol% in the presence of microwave radiations at 400 W (Table 1, entries 10, 11, 12, 13, 14). The
corresponding product was obtained in 60%, 70%, 90%, 98%, and 95% yield respectively. Thus,
the above results showed that the most excellent results were gotten when the reaction was
carried out with 10 mol% of NH4Cl/Zn catalyst in a microwave oven at 400 W for 4 min under
solvent-free conditions.
To investigate the possible reaction pathway controlled experiment was carried out. A
possible reaction mechanism (Scheme 2) has been described on the basis of controlled reaction
and experimental study. Initially, Knoevenagel adduct was obtained by the reaction of 2-
nitrobenzaldehyde and ethyl cyanoacetate which further undergo nucleophilic attack of the
amino group on cyano and subsequent intramolecular cyclization and tautomerization lead to
obtain the final product.
Scheme 2: A plausible mechanism for the synthesis of ethyl 2-aminoquinoline 3-carboxylate.
5
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In the light of the above results, and to show the universality of the reaction (Scheme 1),
the upgraded reaction circumstances were subjected to a variety of benzaldehydes and active
methylene compounds (Scheme 3), and the results were reported (Table 2). It is to be noted that
in all cases, the reaction proceeds smoothly with 10 mol% NH4Cl/Zn catalyst under solvent-free
microwave-assisted condition (Scheme 3). Next, we evaluated the reactivity of various
benzaldehydes bearing electron-withdrawing and electron-donating groups. It was observed that
the condensation of benzaldehydes with electron-withdrawing groups with active methylene
compounds, can be carried out in relatively less time than the benzaldehydes with electron-
donating groups.
Scheme 3: Synthesis of 2,3-disubstituted quinolines.
Table 2: NH4Cl/Zn catalyzed synthesis of 2,3-disubstituted quinoline derivativesa
1
2
3
Time Yieldb
Comp
no
(Reactant)
(Reactant)
(Product)
(min) (%)
3a
3b
4
98
97
4.5
6
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3c
3d
6
4
95
98
3e
3f
4.5
4.5
97
95
3g
6
90
3h
3i
4.5
6
97
90
95
90
3j
4.5
4.5
3k
7
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3l
6
90
aReaction condition: reaction of 1 (10 mmol), 2 (10 mmol) in (NH4Cl/Zn) catalyst (10 mol %)
under microwave-assisted solvent-free condition.
bYields of the isolated products.
To show the superiority of the catalyst (NH4Cl/Zn), the above synthesis (Scheme 1) was
performed with other catalysts and the results are reported (Table 3). Thus, it is concluded that
NH4Cl/Zn (10 mol%) is the most excellent catalyst for the synthesis of the title compound.
Table 3: Investigation of efficiency of various catalyst for the synthesis of quinoline derivatives
Entry Catalyst & Reaction condition Solvent
Time (min) Yielda (%) Reference
1
2
3
4
5
Et3N – heat/150 oC
EtOH
30 min
240 min
12 min
120 min
4 min
80
88
[35]
[36]
PEG-400 – heat/110 oC
PEG-OSO3H – MW
HClO4-SiO2 – heat/ 60 oC
NH4Cl/Zn - MW
No solvent
No solvent
CH3CN
81
90
[37]
[38]
No solvent
98
present work
aYields of the isolated products.
CONCLUSION
Finally, we have demonstrated an eco-friendly, simple, sustainable, economical, and efficient
solvent-free protocol for the preparation of 2,3-disubstituted quinolines by reductive cyclization
of 2-nitrobenzaldehydes and various active methylene compounds via tandem Knoevenagel
condensation under microwave irradiation conditions promoted by NH4Cl/Zn catalyst. This
environmentally acceptable synthetic method provides various benefits like less reaction time,
8
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green condition, product yield is good to excellent, utilizing non-hazard chemicals and all the
chemicals used in the above reactions are commercially affordable. Furthermore, the results
suggest that our environmentally green and sustainable approach by using a solvent-free
microwave-assisted technique leads to higher yields within a very short reaction time.
EXPERIMENTAL
Materials and reagents applied in our experiment were commercially available. Glass TLC plates
coated with Silica Gel-G were used to check the progress of the reaction. The newly synthesized
compounds were purified by column chromatography wherever needed. Open capillary tubes
and a sulfuric acid bath was used to determine the melting points of the synthesized compounds.
FT-IR spectra were obtained with a Shimadzu 8000 spectrophotometer. 1H and 13C NMR spectra
were recorded on a Varian spectrometer. Chemical shifts (δ) are reported in ppm. The
microwave-assisted reactions were carried out in a scientific microwave oven (Catalyst System,
Model No-CATA 2R).
General procedure for the synthesis of Ethyl 2-aminoquinoline-3-carboxylate (3a-l):
In a 50 mL Erlenmeyer Flask a mixture of 1 (2 mmol), 2 (2 mmol), and NH4Cl/Zn (10 mol%)
were taken and the reaction was performed in a microwave oven at 400 W level for a period of 4
min at 5-sec intervals. The confirmation of completion of the reaction was ascertained by TLC
using ethyl acetate-hexane (8:2) as a solvent system. Finally, the reaction mixture was cooled to
room temperature and poured in crushed ice with continuous stirring. The solid product thus
obtained was further, dried, and recrystallized with ethyl acetate-hexane in a volume ratio of
(10:10 mL). The compounds 3b-l were also synthesized by using this same procedure. The
synthesized compounds were subjected to elemental and spectra analysis for the confirmation of
their structures.
Ethyl 2-aminoquinoline-3-carboxylate (3a): Yellow colored solid; mp 133–135 °C; IR
1
(νmax/cm-1): 3418, 1697, 1628, 1288, 1080; H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.85
9
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(dd, J = 8.2, 1.2 Hz, 1H), 7.62 (ddd, J = 8.3, 6.7, 1.6 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.25 (bs,
2H), 7.24 – 7.22 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C-NMR (100 MHz,
DMSO-d6) δ 166.5, 156.7, 150.0, 142.8, 133.0, 129.9, 125.1, 122.7, 122.0, 110.5, 61.6, 14.6.
LCMS: m/z 216 [M+]; Anal. calc. for C12H12N2O2: C, 66.65; H, 5.59; N, 12.69; found: C, 66.69;
H, 5.62; N, 12.72.
1H and 13C NMR spectral data have been provided in supporting information.
ACKNOWLEDGMENTS
The authors are sincerely thankful to Dean of Scientific Research, King Khalid University, Saudi
Arabia, and the College of Pharmacy, department of Pharmaceutical Chemistry.
Funding This work was supported by the Dean of Scientific Research, King Khalid University
for the financial support is greatly appreciated for the General Research Project under grant
number [GRP-238-41].
CONFLICT OF INTEREST The authors confirm that they have no conflict of interest.
ORCID
Syed Tasqeeruddin: https://orcid.org/0000-0002-5253-7606
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