Tetrabutylammonium tribromide: An effective green reagent for the one-pot reaction of 3-acetyl-2H-chromen-2-ones with o-phenylenediamines

Article abstract of DOI:10.24820/ark.5550190.p010.655

An efficient and completely greener approach has been outlined for the reaction of 3-acetyl-2H-chromen-2-ones with o-phenylenediamines using tetrabutylammonium tribromide (TBATB) to obtain 3-(quinoxalin-2-yl)-2H-chromen-2-ones in one-pot. Alternatively, a step-wise method has also been demonstrated for the synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones, where 3-acetyl-2H-chromen-2-ones has first treated with TBATB to give 3-(2-bromoacetyl)-2H-chromen-2-one followed by its nucleophilic substitution reaction with o-phenylenediamines. Use of polyethylene glycol-600 (PEG-600) as the solvent media, mild reaction conditions and easy isolation procedure of products are the added advantages for this synthesis. Both the one-pot and step-wise methods have been compared in terms of their reaction yields and one-pot synthesis was found to be superior. All the synthesized compounds were confirmed by characterization with 1HNMR, 13CNMR, HRMS, IR spectroscopy.

Full text of DOI:10.24820/ark.5550190.p010.655

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2018, part vii, 0-0
Tetrabutylammonium tribromide: an effective green reagent for the one-pot
reaction of 3-acetyl-2H-chromen-2-ones with o-phenylenediamines
Kotthireddy Kavitha,* Devulapally Srikrishna, Pramod Kumar Dubey, and Pasula Aparna
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of Engineering,
Kukatpally, Hyderabad, Telangana - 500 085, India
Email : kavithakothireddy@gmail.com
Received 06-09-2018
Accepted 08-21-2018
Published on line 09-21-2019
Abstract
An efficient and completely greener approach has been outlined for the reaction of 3-acetyl-2H-chromen-2-
ones with o-phenylenediamines using tetrabutylammonium tribromide (TBATB) to obtain 3-(quinoxalin-2-yl)-
2H-chromen-2-ones in one-pot. Alternatively, a step-wise method has also been demonstrated for the
synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones, where 3-acetyl-2H-chromen-2-ones has first treated with
TBATB to give 3-(2-bromoacetyl)-2H-chromen-2-one followed by its nucleophilic substitution reaction with o-
phenylenediamines. Use of polyethylene glycol-600 (PEG-600) as the solvent media, mild reaction conditions
and easy isolation procedure of products are the added advantages for this synthesis. Both the one-pot and
step-wise methods have been compared in terms of their reaction yields and one-pot synthesis was found to
1
be superior. All the synthesized compounds were confirmed by characterization with HNMR, 13CNMR, HRMS,
IR spectroscopy.
O
O
O
R1
O
O
N
N
R2
R1
PEG-600
N
Br3
One-pot Three component
Reaction
TBATB
H2N
H2N
R2
12 Examples
Operational Friendly
Mild Reaction Conditions
Easy Isolation Procedure
Keywords: Tetrabutylammonium tribromide, polyethylene glycol, one-pot method, coumarins, quinoxalines,
green protocol
DOI: https://doi.org/10.24820/ark.5550190.p010.655
Page 1
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Introduction
In the large family of heterocyclic chemistry, coumarin and its derivatives have significant role due to their
distinct applications, abundant availability in nature and various routes for its synthesis. Coumarin is the
effective pharmacophore with wide variety of pharmacological applications.1,2 Some of their important
biological activities include cardiovascular,3 antibiotic,4 anti-viral,5 anti-depressant,6 anti-inflammatory,7 anti-
oxidant,8 antimicrobial,9 etc. Based on their importance and widespread activities, we have recently reviewed
few of the applications of coumarin and its hybrid compounds pertaining to their medicinal chemistry,
material chemistry and agrochemical field.10 Some of the coumarin based drug candidates have listed below
(Figure 1).
N
O
N
N
O
O
O
O
O
O
O
O
O
Ensaculin (KA-672) - Drug for Dementia
Chromonar - vasodilator.
O
OH
O
O
O
HO
O
O
O
N
H
Hymecromone -
antispasmodic drug
Warfarin -
Anticoagualnt
Batoprazine -
antiaggressive agent
Figure 1. Commercially available coumarin based drugs.
Furthermore, quinoxalines and its derivatives have been found to exhibit diversified pharmacological
activities such as anti-inflammatory,11 anti-mycobacterial,12 anti-leishmanial,13 anti-microbial,14 anti-cancer,15
anti-tubercular,16 anti-malarial,17 antibiotic,18 anti-infective,19 etc. Apart from these, quinoxaline derivatives
also exhibited applications such as DNA photo cleaving reagents20 and as dyes.21,22 Some of the commercially
available quinoxaline based drugs have listed in Figure 2.
Br
N
N
H
H
N
N
N
N
NH
N
Varenidine -
Drug to treat Nicotine addiction
Brimonidine -
Anti-hypertensive agent.
O-
N+
S
COOH
O
H
O
N
N
N
N
N
N+
O-
N
H
H
COOH
Carbadox
Quinacillin- Antibiotic
anti-bacterial agent
Figure 2. Commercially available quinoxaline based drugs.
Page 2
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
In the view of importance of coumarin, quinoxaline derivatives, it is worthwhile to synthesize the
compounds containing both the coumarin and quinoxaline rings in a single frame work under environmentally
benign conditions. One of the most commonly used procedures for the synthesis of the quinoxaline ring that
clubbed to coumarin is by the reaction of 3-(2-bromooacetyl)-2H-chromen-2-one with o-phenylenediamines.
Zhou et al. reported23 the synthesis of coumarinylquinoxalines by treating 3-(2-bromoacetyl)-2H-chromen-2-
one with o-phenylenediamine in ethanol under microwave irradiation conditions at 100 °C. Also, Kamble et al.
reported24 the synthesis of coumarin and quinoxaline hybrid derivatives by the reaction of 3-(2-bromoacetyl)-
2H-chromen-2-one with o-phenylenediamine in tetrahydrofuran using pyridine as a catalyst. Thus, in the
preparation of 3-(quinoxalin-2-yl)-2H-chromen-2-ones the common starting material is 3-(2-bromoacetyl)-2H-
chromen-2-one which has to be prepared by the bromination of 3-acetyl-2H-chromen-2-one with bromine.
Conventional methods of bromination of organic substrates mostly use liquid bromine as brominating reagent.
However, bromine is a corrosive toxic reagent, maintenance of stoichiometry is difficult, special care is
required for its storage, handling and transportation, it is very important for many organic transformations.
Therefore there has been a search for benign reagents which can act as bromine alternatives. Among all the
bromine alternatives that have been developed so far, a group of reagents that have become popular are the
quaternary ammonium tribromides which are finding numerous applications in various bromination
reactions.25,26 Among all these, tetrabutylammonium tribromide (TBATB) has attracted the attention of
researchers because of its stability, easier method of preparation and its advantages over liquid bromine such
as its use at higher temperature.27,28
One-pot method of synthesis constitute one of the most effective tools in emerging organic chemistry,
since they have features that contribute to an ideal synthesis such as atom economy, rapid and easy
implementation, energy and time saving, eco-friendly methods with target and diversity-oriented synthesis.29
Development of new one-pot reactions towards pharmacologically active scaffolds is inevitable at the present
time whereby a starting material is subjected to successive chemical operations in a single reaction vessel. So,
with the above literature precedence, herein we wish to report an efficient environmentally benign one-pot
method for the synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones using TBATB as the reagent by the direct
reaction of 3-acetyl-2H-chromen-2-ones with o-phenylenediamines.
Results and Discussion
As shown in Scheme 1, reaction of commercially available salicylaldehydes with ethyl acetoacetate in ethanol
containing catalytic amount of piperidine as a catalyst at room temperature (RT) for 2 h afforded 3-acetyl-2H-
chromen-2-ones (1). Bromination of the latter with TBATB in PEG-600 at RT for 1 ½ h resulted in the formation
of 3-(2-bromoacetyl)-2H-chromen-2-ones (2) (Scheme 1).
Scheme 1. Synthesis of 3-(2-bromoacetyl)-2H-chromen-2-one (2) starting from salicylaldehydes
Page 3
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Reaction of 3-(2-bromoacetyl)-2H-chromen-2-one (2a, i.e., 2, R1=H), with equimolar amount of o-
phenylenediamine (3a, i.e., 3, R2=H) in PEG-600 at 100 °C for 45 min. resulted in the formation of 3-
(quinoxalin-2-yl)-2H-chromen-2-one (4a, i.e., 4, R1=R2=H) (Scheme 2).
O
O
PEG-600 / 100 0C
45 min.
O
O
O
H2N
H2N
N
N
+
Br
2a
3a
4a
Scheme 2. Synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-one (4a) from 2a & 3a.
In order to check the effect of solvent on this reaction, several solvents have been screened to get the
product 4a in shorter time with maximum yield. When this reaction has been carried out using different
solvents, resulted in the formation of product 4a, but none of them were superior to PEG-600 (Table 1).
Optimization data with several solvents has revealed that this reaction was found to complete very smoothly
when PEG-600 was used as a reaction media in terms of product yield and reaction time (Table 1).
Table 1. Optimization of reaction conditions for the synthesis of 4a from 2a & 3a
S. No.
Solvent
PEG-600
Isopropyl alcohol
Ethylene glycol
Glycerol
Reaction condition
100 °C
83 °C
Reaction Time
45 min.
2.5 h
2 h
Yield# (%)
89
1
2
3
4
5
66
76
79
74
100 °C
100 °C
78 °C
1.5 h
2h
Ethanol
6
7
Acetonitrile
Methanol
82 °C
65 °C
2.5 h
3 h
70
68
8
9
10
Tetrahydrofuran
1,4-dioxane
Acetone
66 °C
101 °C
56 °C
2.5 h
2 h
4.5 h
65
62
58
# isolated yield
Having optimized the reaction conditions in hand, this protocol was generalized and was successfully
extended to other derivatives of 3-(2-bromoacetyl)-2H-chromen-2-ones (2) and o-phenylenediamines (3)
(Scheme 3).
Page 4
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Scheme 3. Synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones (4a-l).
Encouraged with the above results, we thought of interest to prepare these compounds in a one-pot
method from 3-acetyl-2H-chromen-2-ones (1). For this, in a blank experiment, we have taken equimolar
amounts of 3-acetyl-2H-chromen-2-one (1a) and o-phenylenediamine (3a) and heated to 100 °C in PEG-600 to
check whether any reaction taking place between 1a and 3a to form Schiff’s base under our reaction
conditions. We observed no product formation between these two reactants and the starting materials were
recovered (Scheme 4).
O
O
PEG-600 / 100 0C
2 h
O
O
O
H2N
H2N
+
N
H2N
1a
3a
Scheme 4. Attempted reaction for the possibility of Schiff’s base between 1a & 3a.
With the above experiment, we understood that there is no problem of Schiff’s base formation and this
has been taken as an advantage, tried to prepare the target compounds in a one-pot method using TBATB as
the bromine source for in-situ α-bromination of 1. Thus equimolar amounts of 3-acetyl-2H-chromen-2-one
(1a), TBATB and o-phenylenediamine (3a) were reacted together in PEG-600 at 100 °C for 1 h. Interestingly,
this reaction was successfully completed and gave the desired product i.e., 3-(quinoxalin-2-yl)-2H-chromen-2-
one (4a). Thus, we have extended the scope of this one-pot protocol for various 3-acetyl-2H-chromen-2-ones
(1) and o-phenylenediamines (4) to obtain the required quinoxalines (4a-l) in excellent yields. (Scheme 5).
Page 5
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Scheme 5. One-pot synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones (4a-l) from 1.
The mechanism for this one-pot reaction was studied and here TBATB can be considered as a general
brominating agent where it reacts with 3-acetyl-2H-chromen-2-one (1) in PEG-600 to give the corresponding
3-(2-bromoacetyl)-2H-chromen-2-one (2), HBr and tetrabutylammonium bromide (TBAB). 2 thus, formed in
this way can be readily reacted in situ with o-phenylenediamines (4) to give the corresponding quinoxalines 4.
The beauty of this reaction is that TBATB during its reaction generates TBAB, which will be in the reaction
mass, and will then act as a Phase Transfer Catalyst (PTC) and enhance the progress of the condensation
reaction (alkylation of 3 by bromoacetyl group) between 2 & 3 in-situ (Scheme 6). In detail, α-bromoacetyl
group of 2 initially undergo nucleophilic substitution reaction with one of the amine from o-phenylenediamine
(3) to form a condensed product “A”. Another amine from this condensed compound “A” will undergo
internal nucleophilic addition reaction with carbonyl carbon to form a cyclized compound “B” which will
undergo dehydration to form “C”. The latter being the dihydroderivative, quite unstable, undergoes
dehydrogenation (oxidation) under heating conditions to yield the thermally stable, aromatized product
quinoxaline 4.
O
O
O
O
2
O
O
Bu4NBr
(TBAB)
Bu4NBr3
(TBATB)
PEG-600
+
+ HBr
+
Br
1
works as PTC & enhances
the condensation reaction
between 2 & 3a
O
O H2N
N
O
O
O
O
O H2N
H2N
-HBr
+
Br
N
H2N
3a
H
O
H
O
A
H
2
Br
O
O
O
O
O
O
O
O
H
N
H
N
H
N
N
N
HO
O
N
H
N
H
N
H
4
C
B
Scheme 6. Plausible mechanism for the formation of 3-(quinoxalin-2-yl)-2H-chromen-2-one (4).
Page 6
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
The overall yield from the stepwise synthesis for the formation of 4 has been calculated (Table 2) and
compared with the yield of 4 obtained from the one-pot synthesis (Figure 3). From this comparison, it can be
concluded that one-pot synthesis is the most convenient and efficient method for the preparation of these
quinoxalines.
Table 2. Comparison of yields of 4 obtained in step-wise & One-pot method
S. No.
Step-Wise method
Yield of 4
from 2 & 3
4a: 88
Yield of 4 obtained
in One-pot method
Yield of 2
from 1
2a: 93
2a: 93
2a: 93
2a: 93
2a: 93
2a: 93
2b: 89
2b: 89
2b: 89
2b: 89
2b: 89
2b: 89
Overall
yield of 4
4a: 82
4b: 70
4c: 67
4d: 78
4e: 72
4f: 75
4g: 69
4h: 67
4i: 65
4j: 73
4k: 71
4l: 70
1
2
3
4
5
6
7
8
9
4a: 90
4b: 77
4c: 76
4d: 87
4e: 84
4f: 83
4g: 78
4h: 75
4i: 77
4j: 89
4k: 82
4l: 85
4b: 76
4c: 73
4d: 84
4e: 77
4f: 81
4g: 78
4h: 75
4i: 73
10
11
12
4j: 82
4k: 80
4l: 79
Figure 3. Yield comparison of step-wise as well as one-pot method for the synthesis of 4.
Synthesis of TBATB
A mixture of TBAB (38.80 g, 120 mmol), sodium bromate (6.00 g, 40 mmol) and water (300 mL) was stirred at
room temperature for 10 min. To this solution was added 48% Aq. HBr (28 mL) drop wise under stirring and
continued for another 30 min at room temperature. An orange colored solid precipitated out, which was
filtered, washed with water (2×120 mL) and air-dried at room temperature.
Yield: 55.36 g (96%). mp 74-76°C.
Page 7
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Characterization of TBATB
Formation of the reagent TBATB was compared with the available literature data, however, further
characterization is always an added advantage. In view of this, we have characterized TBATB with powder
XRD, SEM–EDX, DSC and TG/DTA analysis.
SEM–EDX analysis of TBATB
The surface morphology of TBATB was studied by recording its SEM micrograph. These SEM images (Figure 4)
showed proper alignment and an even distribution which was recorded at different magnifications. Further,
the elemental composition of the material has been came to know with the help of EDX analysis (Figure 5). For
this reagent, EDX analysis showed the presence of C, N and Br elements.
Figure 4. SEM image of TBATB at different magnifications.
Figure 5. EDX analysis of TBATB.
Page 8
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
Powder X-ray diffraction (XRD) analysis of TBATB
The nature of the prepared TBATB was identified by recording its powder XRD. X-ray patterns of TBATB was
recorded at 2 theta = 10–80° range (Figure 6). A broad peak centered at 2 theta angle showed the strong
crystalline peaks in the range of 10–60° confirmed the TBATB reagent as crystalline in nature.
Figure 6. Powder X-ray diffraction analysis of TBATB.
TG/DTA analysis of TBATB
Further the scope and the stability of the reagent at higher temperatures were studied by TG-DTA analysis.
DSC measures amount of energy released or absorbed by the sample when it is cooled or heated, providing
quantitative and qualitative data on endothermic (heat absorption) and exothermic (heat evolution) processes
and the main advantage of DSC is to measure melting temperature. The melting endotherm for TBATB after
heating is shown an enthalpy of 278.6 J/g (Figure 7).
Figure 7. DSC curve of TBATB.
Differential thermal analysis (DTA) and thermo gravimetric analysis (TGA) of the prepared reagent, i.e.,
TBATB has also been carried out simultaneously. Thermal stability of the reagent was tested by heating the
Page 9
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
reagent at a rate of 5°C /min under inert nitrogen atmosphere. In DTA curve, the first endothermic peak at 75
°C is due to its meting point, which is also evident from the DSC curve. Another important observation in TGA
is there was no phase transition observed till the material melts which showed that this reagent can withstand
higher temperatures (Figure 8).
Figure 8. TG-DTA curves of TBATB.
Conclusions
In conclusion, we have established an efficient one-pot three component method for the synthesis of 3-
(quinoxalin-2-yl)-2H-chromen-2-ones in PEG-600 as the green reaction media. This one-pot method worked
very efficiently and effectively for the synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones by cutting down the
number of steps, lowering the reaction time and relieving from the difficulty of isolating the compounds in
every step and their purifications. The method applied for this synthesis is regarded as environmentally
harmless by avoiding the harmful toxic chemical, i.e., liquid bromine, and the harmful carcinogenic solvents.
Synthesis carried in stepwise process also and compared the yield of the products among the two methods
and the one-pot method found to be superior among the two. The exploration of bromine alternative lead us
to a safe, easily handlable reagent i.e., TBATB, which is paved a way for the emerging researchers in the
particular field of interest.
Experimental Section
General. Melting points are uncorrected and were determined in open capillary tubes using sulphuric acid
bath. TLC analyses were done on silica gel-G coated sheets supplied by Merck Company and visualization was
Page 10
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
done using UV lamp and iodine. 1H NMR spectra were recorded in DMSO–d6 using TMS as an internal standard
using 400 MHz spectrometer. Mass spectra were recorded on Agilent-LCMS instrument. Starting materials like
salicylaldehyde, ethyl acetoacetate, o-phenylenediamines were purchased from commercial suppliers and
used as such.
General procedure for the preparation of 2 from 1. A mixture of 1 (20 mmol), TBATB (20 mmol), PEG-600 (30
mL) was stirred at RT for 1 – 1 ½ h. After completion of the reaction, the mixture was poured into ice-cold
water (60 mL). The separated solid was filtered, washed with water (2×30 mL) and air-dried at RT. The crude
product was recrystallized from suitable solvent to obtain pure 2.
3-(2-Bromoacetyl)-2H-chromen-2-one (2a): White color solid. Yield: 4.96 g (93 %). mp: 165-167 °C [23]; IR
1
(KBr) vmax/cm-1: 1717 cm-1 (strong, sharp, -CO of coumarin ring), 1683 (CO of -COCH3); H-NMR (400 MHz,
DMSO-d6/ TMS): δ 4.68 (s, 2H, -CH2), 7.35-8.00 (complex, multiplet, 4H, Ar-H), 8.68 (s, 1H, Ar-H); 13C-NMR (100
MHz, DMSO-d6): 36.3, 116.2, 118.2, 122.8, 125.1, 131.0, 135.0, 148.5, 152.3, 163.6, 190.3; HRMS calculated for
C11H7BrO3 [M+H]+: 266.9656, found: 266.9697.
3-(2-Bromoacetyl)-6-nitro-2H-chromen-2-one (2b). White color solid. Yield: 5.55 g (89 %). mp: 145-147 °C
1
[23]; IR (KBr) vmax/cm-1: 1726 cm-1 (strong, sharp, -CO of coumarin ring), 1685 (CO of -COCH3); H-NMR (400
MHz, DMSO-d6/ TMS): δ 4.80 (s, 2H, -CH2), 7.35-7.54 (complex, multiplet, 2H, Ar-H), 7.98 (s, 1H, Ar-H), 8.68 (s,
13
1H, Ar-H); C-NMR (100 MHz, DMSO-d6): 36.5, 116.5, 118.8, 122.8, 125.6, 132.0, 140.8, 148.8, 153.2, 164.2,
190.9; HRMS calculated for C11H6BrNO5 [M+H]+: 311.9507, found: 311.9576.
General procedure for the synthesis of 4 from 2 & 3. A mixture of 2 (10 mmol), 3 (10 mmol) in PEG-600
(20 mL) was heated to 100 °C and maintained for a period of 30 min. to 1 h. After completion of the reaction,
the mixture was poured into ice-cold water (60 mL). The separated solid was filtered, washed with water
(2×30 mL) and air-dried at RT. The crude product was recrystallized from suitable solvent to obtain pure 4.
3-(Quinoxalin-2-yl)-2H-chromen-2-one (4a). Brown color solid. Yield: 2.41 g (88%); mp: 198-200 °C
(Methanol); IR (KBr) vmax/cm-1: 1715 cm-1 (strong, sharp, -CO of coumarin ring); 1H-NMR (400 MHz, DMSO-d6/
13
TMS): δ 7.34-8.36 (complex, multiplet, 8H, Ar- H), 8.87 (s, 1H, Ar-H), 9.55 (s, 1H, Ar-H ); C-NMR (100 MHz,
DMSO-d6): 116.1, 119.0, 123.5, 124.9, 128.8, 129.0, 129.7, 130.5, 130.7, 133.2, 141.2, 144.5, 145.3, 147.7,
153.8, 159.5; HRMS calculated for C17H10N2O2 [M+H]+: 275.08205, found: 275.0821.
3-(7-Methylquinoxalin-2-yl)-2H-chromen-2-one (4b). Brown color solid. Yield: 2.18 g (76%); mp: 190-192 °C
1
(Ethanol); IR(KBr) νmax/ cm-1: 1715 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz, DMSO-d6/
TMS): δ 2.43 (s, 3H, CH3), 7.38-8.12 (complex, m, 7H, Ar-H), 8.83 (s, 1H, Ar-H), 9.54 (s, 1H, Ar-H); 13C NMR (100
MHz, DMSO-d6): 21.3, 116.0, 119.0, 124.9, 127.6, 128.3, 128.5, 129.6, 133.1, 139.7, 140.9, 141.4, 144.1, 144.3,
145.1, 147.4, 153.7, 159.5; HRMS calculated for C18H12N2O2 [M+H]+: 289.09710, Found: 289.09662.
3-(7-Methoxyquinoxalin-2-yl)-2H-chromen-2-one (4c). Brown color solid. Yield: 2.21 g (73%); mp: 156-158 °C
1
(Ethanol); IR(KBr) νmax/ cm-1: 1720 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz, DMSO-d6/
TMS): δ 3.96 (s, 3H, OCH3), 7.43-8.06 (complex, m, 7H, Ar-H), 8.90 (s, 1H, Ar-H), 9.52 (s, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6): 51.3, 117.5, 117.6, 128.3, 128.5, 129.6, 130.7, 132.7, 132.8, 133.1, 134.4, 139.7, 140.8,
141.4, 144.0, 144.3, 155.1, 167.0; HRMS calculated for C18H12N2O3 [M+H]+: 305.09261, Found: 305.09245.
3-(7-Nitroquinoxalin-2-yl)-2H-chromen-2-one (4d). Brown color solid. Yield: 2.67 g (84%); mp: 240-242 °C
(Methanol); IR(KBr) νmax/ cm-1: 1723 cm-1 (strong, sharp, -CO of coumarin ring); 1H NMR (400 MHz, DMSO-d6/
TMS): δ 7.44-8.06 (complex, m, 7H, Ar-H), 8.91 (s, 1H, Ar-H), 9.55 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6):
127.6, 128.3, 128.5, 129.6, 130.7, 132.7, 132.8, 133.1, 134.4, 139.7, 141.4, 144.3, 145.1, 147.0, 147.4, 153.7,
159.5; HRMS calculated for C17H9N3O4 [M+H]+: 320.06713, Found: 320.06728.
Page 11
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
3-(7-Fluoroquinoxalin-2-yl)-2H-chromen-2-one (4e). Brown color solid. Yield: 2.25 g (77%); mp: 167-169 °C
(Methanol); IR(KBr) νmax/ cm-1: 1725 cm-1 (strong, sharp, -CO of coumarin ring), 1H NMR (400 MHz, DMSO-d6/
TMS): δ 7.44-8.06 (complex, m, 7H, Ar-H), 8.90 (s, 1H, Ar-H), 9.55 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6):
127.7, 128.3, 128.5, 129.6, 132.7, 132.8, 133.1, 139.7, 140.9, 141.2, 141.4, 144.1, 144.3, 145.1, 147.5, 153.7,
159.5; HRMS calculated for C17H9FN2O2 [M+H]+: 293.07263, Found: 293.07219.
3-(7-Chloroquinoxalin-2-yl)-2H-chromen-2-one (4f). Brown color solid. Yield: 2.50 g (81%); mp: 185-187 °C
1
(Acetone); IR(KBr) νmax/ cm-1: 1718 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz, DMSO-d6/
TMS): δ 7.43-8.07 (complex, m, 7H, Ar-H), 8.89 (s, 1H, Ar-H), 9.56 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6):
126.9, 127.7, 128.2, 128.9, 131.9, 132.2, 132.9, 138.2, 140.5, 141.2, 141.8, 143.9, 144.1, 144.9, 146.9, 152.6,
158.8; HRMS calculated for C17H9ClN2O2 [M+H]+: 309.04308, Found: 309.04299.
6-Nitro-3-(quinoxalin-2-yl)-2H-chromen-2-one (4g). Yellow color solid. Yield: 2.48 g (78%); mp: 247-249 °C
1
(Ethanol); IR (KBr) vmax/cm-1: 1712 cm-1 (strong, sharp, -CO of coumarin ring); H-NMR (400 MHz, DMSO-d6/
13
TMS): δ 7.67-8.39 (complex, multiplet, 7H, Ar- H), 8.88 (s, 1H, Ar-H), 9.60 (s, 1H, Ar-H ); C-NMR (100 MHz,
DMSO-d6): 118.4, 123.4, 124.5, 124.5, 128.8, 129.0, 129.5, 129.7, 129.7, 142.2, 143.2, 144.3, 144.4, 146.7,
153.8, 159.5, 161.7; HRMS calculated for C17H9N3O4 [M+H]+: 320.06713, Found: 320.06245.
3-(7-Methylquinoxalin-2-yl)-6-nitro-2H-chromen-2-one (4h): Yellow color solid. Yield: 2.66 g (80%); mp: 202-
1
204 °C (Methanol); IR(KBr) νmax/ cm-1: 1734 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz,
DMSO-d6/ TMS): δ 2.43 (s, 3H, CH3), 7.58-8.52 (complex, m, 6H, Ar-H), 8.83 (s, 1H, Ar-H), 9.54 (s, 1H, Ar-H); 13C
NMR (100 MHz, DMSO-d6): 21.3, 118.0, 123.0, 124.6, 124.9, 127.3, 128.5, 129.6, 134.1, 138.7, 139.9, 141.4,
142.1, 144.3, 146.1, 153.4, 159.7, 161.5; HRMS calculated for C18H11N3O4 [M+H]+: 334.08278, Found:
334.08098.
3-(7-Methoxyquinoxalin-2-yl)-6-nitro-2H-chromen-2-one (4i). Yellow color solid. Yield: 2.75 g (79%); mp: 192-
1
194 °C (Methanol); IR(KBr) νmax/ cm-1: 1724 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz,
DMSO-d6/ TMS): δ 3.86 (s, 3H, OCH3), 7.53-8.56 (complex, m, 6H, Ar-H), 8.87 (s, 1H, Ar-H), 9.52 (s, 1H, Ar-H);
13C NMR (100 MHz, DMSO-d6): 55.3, 103.5, 118.6, 123.3, 124.5, 124.6, 127.7, 129.8, 130.7, 137.8, 140.1, 144.4,
144.7, 146.8, 154.6, 158.4, 159.0, 161.3; HRMS calculated for C18H11N3O5 [M+H]+: 350.07769, Found:
350.07812.
6-Nitro-3-(7-nitroquinoxalin-2-yl)-2H-chromen-2-one (4j). Yellow color solid. Yield: 2.98 g (82%); mp: 258-260
1
°C (Acetone); IR(KBr) νmax/ cm-1: 1712 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz, DMSO-
d6/ TMS): δ 7.64-8.56 (complex, m, 6H, Ar-H), 8.91 (s, 1H, Ar-H), 9.55 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO-
d6): 127.6, 128.3, 128.5, 129.6, 130.7, 132.7, 132.8, 133.1, 134.4, 139.7, 141.4, 144.3, 145.1, 147.0, 147.4,
153.7, 159.5; HRMS calculated for C17H8N4O6 [M+H]+: 365.05221, Found: 365.05011.
3-(7-Fluoroquinoxalin-2-yl)-6-nitro-2H-chromen-2-one (4k). Yellow color solid. Yield: 2.59 g (77%); mp: 231-
1
233 °C (Methanol); IR(KBr) νmax/ cm-1: 1708 cm-1 (strong, sharp, -CO of coumarin ring), H NMR (400 MHz,
DMSO-d6/ TMS): δ 7.44-8.56 (complex, m, 6H, Ar-H), 8.90 (s, 1H, Ar-H), 9.55 (s, 1H, Ar-H); 13C NMR (100 MHz,
DMSO-d6): 127.7, 128.3, 128.5, 129.6, 132.7, 132.8, 133.1, 139.7, 140.9, 141.2, 141.4, 144.1, 144.3, 145.1,
147.5, 153.7, 159.5; HRMS calculated for C17H8FN3O4 [M+H]+: 338.05771, Found: 338.05842.
3-(7-Chloroquinoxalin-2-yl)-6-nitro-2H-chromen-2-one (4l). Yellow color solid. Yield: 2.78 g (79%); mp: 215-
1
217 °C (Ethanol); IR(KBr) νmax/ cm-1: 1714 cm-1 (strong, sharp, -CO of coumarin ring); H NMR (400 MHz,
DMSO-d6/ TMS): δ 7.41-8.56 (complex, m, 6H, Ar-H), 8.85 (s, 1H, Ar-H), 9.56 (s, 1H, Ar-H); 13C NMR (100 MHz,
DMSO-d6): 68.3, 111.4, 115.8, 120.0, 125.9, 127.7, 129.2, 130.9, 131.9, 139.2, 139.9, 140.2, 142.5, 143.2,
143.8, 154.9, 163.7; HRMS calculated for C17H8ClN3O4 [M+H]+: 354.02816, Found: 354.02924.
General procedure for the one-pot three component synthesis of 4 from 1 & 3. A mixture of 1 (10 mmol),
TBATB (10 mmol), 3 (10 mmol) and PEG-600 (20 mL) was heated to 100 °C and maintained at the same
Page 12
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
temperature for a period of 1-2 h. Progress of the reaction was monitored on TLC. After completion of
reaction, the mixture was poured into ice-cold water (60 mL). The separated solid was filtered, washed with
water (2×30 mL) and dried. The crude product was recrystallized from a suitable solvent to obtain pure 4.
Acknowledgements
Authors are sincerely thankful to the authorities of Jawaharlal Nehru Technological University Hyderabad, for
providing laboratory facilities to carry out the research work. One of the author (KK) is grateful for the
financial support in the form of Lectureship.
Supplementary Material
Characterization data (for all new products), copies of 1H and 13C NMR, HRMS and IR spectra are reported in
the Supplementary Material associated with this paper.
References
1. Venugopala, K. N.; Rashmi, V.; Odhav, B. Biomed Res. Int. 2013, 43, 1-14.
http://dx.doi.org/10.1155/2013/963248
2. Atul, M.; Alpeshkumar, M.; Jitender, V.; Vijay, V.; Arun, M.; Kuldip, U. Eur. J. Med. Chem. 2008, 43, 2395-
2403.
https://doi.org/10.1016/j.ejmech.2008.01.016
3. Manolov, I.; Danchev, N.D. Eur. J. Med. Chem. 1995, 30, 531-535.
https://doi.org/10.1016/0223-5234(96)88266-3
4. Schio, L.; Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543-1547.
https://doi.org/10.1016/S0040-4039(99)02351-5
5. Hwu, J. R.; Lin, S. Y.; Tsay, S. C.; De, C. E.; Leyssen, P.; Neyts, J. J. Med. Chem. 2011, 54, 2114-2126.
https://pubs.acs.org/doi/abs/10.1021/jm101337v
6. Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem.
Lett. 2011, 21, 1937-1941.
https://doi.org/10.1016/j.bmcl.2011.02.040
7. Bansal, Y.; Sethi, P.; Bansal, G. Med. Chem. Res. 2013, 22, 3049-3060.
https://link.springer.com/article/10.1007%2Fs00044-012-0321-6
8. Kostova, I.; Bhatia, S.; Grigorov, P.; Balkansky, S.; Parmar, V. S.; Prasad, A. K. Curr. Med. Chem. 2011, 18,
3929-3951.
http://www.eurekaselect.com/74870/article
9. Ostrov, D. A.; Hernandez, P. J. A.; Corsino, P. E.; Finton, K. A.; Le, N.; Rowe, T. Chemother. 2007, 51, 3688-
3698.
http://aac.asm.org/content/51/10/3688.full.pdf+html
10. Kavitha, K.; Aparna, P. RJLBPCS. 2018, 4, 204-224.
http://www.rjlbpcs.com/article-pdf-downloads/2018/18/219.pdf
Page 13
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Kavitha, K. et al.
11. Burguete, A.; Pontiki, E.; Hadjipavlou, L. D.; Ancizu, S.; Villar, R.; Solano, B.; Moreno, E; Torres, E.; Perez, S.;
Aldana, I.; Monge, A. Chem. Biol. Drug. Des. 2011, 77, 255–267.
https://doi.org/10.1111/j.1747-0285.2011.01076
12. Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45, 5604-5606.
https://pubs.acs.org/doi/abs/10.1021/jm020310n
13. Guillon, J.; Forfar, I.; Mamani, M. M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger,
J. M.; Dufaure, B.; Haumont, G.; Jarrya, C.; Mossalay, D. Bioorg. Med. Chem. 2007, 15, 194–210.
https://doi.org/10.1016/j.bmc.2006.09.068
14. Tandon, V. K.; Yadav, B. D.; Maurya, H. K.; Chaturvedi, A. K.; Shukla, P. K. Bioorg. Med. Chem. 2006, 14,
6120–6126.
https://doi.org/10.1016/j.bmc.2006.04.029
15. Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A. Bioorg. Med. Chem. 2004, 12, 3711–3721.
https://doi.org/10.1016/j.bmc.2004.04.013
16. Waring, M. J.; Ben, H. T.; Kotchevar, A. T.; Ramdani, A.; Touzani. R.; Elkadiri, S.; Hakkou, A.; Bouakka,
M.; Ellis, T. Molecules 2002, 7, 641-656.
https://pdfs.semanticscholar.org/5951/fa5e845e784592c4e5e675fe73c64d6f1d04.pdf
17. Vicente, E.; Lima, L. M.; Bongard, E.; Charnaud, S.; Villar, R.; Solano, B.; Burguete, A.; Perez, S. S.; Aldana,
I.; Vivas, L.; Monge, A. Eur. J. Med. Chem. 2008, 43, 1903-1910.
https://doi.org/10.1016/j.ejmech.2007.11.024
18. Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. 2004, 14, 541-544.
https://doi.org/10.1016/j.bmcl.2003.09.086
19. Jampilek, J. Curr. Med. Chem. 2014, 21, 4347-73.
http://www.eurekaselect.com/125230/article
20. Toshima, K.; Takano, K.; Ozawa, T. Chem. Commun. 2002, 212-213.
http://pubs.rsc.org/en/content/articlelanding/2002/cc/b107829c#!divAbstract
21. Sonawane, N. D.; Rangnekar, D. Heterocycl. Chem. 2002, 39, 303-308.
https://doi.org/10.1002/jhet.5570390210
22. Katoh, A.; Yoshida, T. Heterocycles 2000, 52, 911-920.
https://heterocycles.jp/newlibrary/payments/form/07767/PDF
23. Zhou, J. F.; Gong, G. X.; An, L. T.; Liu, Y.; Zhu, Y. X.; Zhu, Y. L. Synlett 2008, 20, 3163-3166.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0028-1087280
24. Atulkumar, A. K.; Ravindra, R. K.; Mahadev, N. K.; Gireesh, T. Med. Chem. Res. 2016, 25, 1163-1174.
https://link.springer.com/article/10.1007/s00044-016-1558-2
25. Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70, 4267-4271.
https://pubs.acs.org/doi/abs/10.1021/jo050059u
26. Kumar, A.; Alimenla, B.; Jamir, L.; Sinha, D.; Sinha, U. B. Org. Commun. 2012, 5, 64-69
http://www.acgpubs.org/OC/2012/Volume%205/Issue%201/8-OC-1111-221.pdf
27. Bora, U.; Chaudhuri, M. K.; Dey, D.; Dhar, S. S. Pure Appl. Chem. 2001, 73, 93–102.
https://doi.org/10.1351/pac200173010093
28. Hazarika, S.; Gogoi, P.; Barman, P. RSC Adv. 2015, 5, 25765-25767.
http://pubs.rsc.org/en/content/articlelanding/2015/ra/c5ra00677e#!divAbstract
29. Yujiro, H. Chem. Sci. 2016, 7, 866-880.
http://pubs.rsc.org/en/content/articlelanding/2016/sc/c5sc02913a#!divAbstract
Page 14
©ARKAT USA, Inc