PEG-assisted one-pot three-component synthesis of 1,3-oxazino quinoline and chromeno 1,3-oxazin derivatives under catalyst free condition

Article abstract of DOI:10.1080/00397911.2020.1737129

A straightforward and greener PEG-assisted protocol has been disclosed for the cascade synthesis of [1,3]Oxazino quinoline, and chromeno[1,3]oxazin derivatives via three component reaction of multifarious aromatic amines with formaldehyde and 4-hydroxyquinoline-2(1H)-one or 4-methylumbelliferone by using very convenient reaction conditions. This methodology represents a sustainable approach for rapid access to a library of diversity oriented highly pure [1,3]oxazino scaffolds with broad substrate scope.

Full text of DOI:10.1080/00397911.2020.1737129

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
PEG-assisted one-pot three-component synthesis
of 1,3-oxazino quinoline and chromeno 1,3-oxazin
derivatives under catalyst free condition
Maruti B. Yadav, Sandip Gangadhar Balwe, Jong Tae Kim, Byung Gwon Cho &
Yeon Tae Jeong
To cite this article: Maruti B. Yadav, Sandip Gangadhar Balwe, Jong Tae Kim, Byung Gwon
Cho & Yeon Tae Jeong (2020): PEG-assisted one-pot three-component synthesis of 1,3-
oxazino quinoline and chromeno 1,3-oxazin derivatives under catalyst free condition, Synthetic
Communications, DOI: 10.1080/00397911.2020.1737129
To link to this article: https://doi.org/10.1080/00397911.2020.1737129
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https://doi.org/10.1080/00397911.2020.1737129
PEG-assisted one-pot three-component synthesis of 1,3-
oxazino quinoline and chromeno 1,3-oxazin derivatives
under catalyst free condition
Maruti B. Yadav, Sandip Gangadhar Balwe, Jong Tae Kim, Byung Gwon Cho, and
Yeon Tae Jeong
Department of Image Science and Engineering, Pukyong National University, Busan, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 15 October 2019
A straightforward and greener PEG-assisted protocol has been dis-
closed for the cascade synthesis of [1,3]Oxazino quinoline, and chro-
meno[1,3]oxazin derivatives via three component reaction of
multifarious aromatic amines with formaldehyde and 4-hydroxyqui-
noline-2(1H)-one or 4-methylumbelliferone by using very convenient
reaction conditions. This methodology represents a sustainable
approach for rapid access to a library of diversity oriented highly
pure [1,3]oxazino scaffolds with broad substrate scope.
KEYWORDS
Chromeno 1,3-oxazin;
multicomponent reactions
(MCRs); [1,3]oxazino
quinoline; polyethylene
glycol (PEG-600)
GRAPHICAL ABSTRACT
Introduction
In recent years, the development of synthetic chemistry has gained considerable interest
in the area of academia, industrial, and pharmaceutical research.[1–2] Synthetic chemists
have aimed to replace organic solvent as a reaction media with environmentally accept-
able alternatives such as ionic liquid, water, PEG and carried out the reaction under
solvent-free condition.[3] Catalyst-free synthetic approaches are also a remarkable tool
in scientific society because they have a minimum cost, less problematic in purity, and
pollution.[4] Polyethylene glycol (PEG) is a greener alternative in organic synthesis as it
has become more favorable over toxic organic solvents due to nontoxicity, bio-
compatibility, bio-degradability, and miscibility of aqueous or nonaqueous solvent.[5]
Furthermore, the application of PEGs as reaction media for the multicomponent
reactions (MCRs) also will be beneficial from the recent innovation in employing bio-
CONTACT Yeon Tae Jeong
ytjeong@pknu.ac.kr
Department of Image Science and Engineering, Pukyong
National University, Busan 48513, Republic of Korea.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
M. B. YADAV ET AL.
Scheme 1. Synthesis of [1,3]Oxazino quinoline (4) and chromeno 1,3-oxazin (6) derivatives.
based chemicals as green solvents.[6] The combination of MCRs and PEGs as a solvent
has enhanced a new research direction, which enables simultaneous growth of both
MCRs and green solvent toward ideal organic synthesis.[7–10] However, multicomponent
reactions (MCRs) are extremely ideal and eco-friendly reaction method and the targeted
compounds can be achieved in significantly fewer steps. Due to the advantages of pro-
viding sufficient structural diversity, atom economy,[11] molecule complexity,[12] and
simple operation the MCRs have been widely used in drug discovery, biology, and nat-
ural product synthesis.[13]
Quinoline alkaloids are usually isolated from plant Rutaceae,[14–19] it has been reported
that the quinoline alkaloids exhibit an active wide range of biological properties.[20] This
active wide range of biological properties has stimulated interest in the synthesis of quinoli-
none moieties.[21–25] The importance of 1,3-oxazine molecule has been increased because a
compound containing the 1,3-oxazine ring system has exhibited a wide spectrum of
pharmacological activities, such as anti-bacterial,[26,27] anti-tumor,[28] anti-malarial,[29] and
anti-oxidant activities.[30–33] Very lately, Zhou et al. have reported 1,3-oxazine molecule
under the catalytic (ZrOCl2ꢀ8H2O) condition,[34,35] which is for the environmental perspec-
tive using of catalyst is unfriendly. Being a part of our continued interests not to make the
environment hostile, in this synthesis of heterocyclic compounds and green chemistry[36–40]
we have explored for the PEG-assisted approach and catalyst-free synthesis of [1,3]oxa-
zine[5,6-c]quinoline-5-one, and 4-methyl-9-phenylchromeno[8,7-e][1,3] oxazine-2(8H)-one
derivatives under the mild reaction condition (Scheme 1).
Result and discussion
For the introductory investigation, the reaction of 4-hydroxyquinoline-2-(1H)-one (3a),
aniline (1a), and formaldehyde (2a) in ethanol has been chosen as a simple model

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3
strategy (Scheme 2). The reaction mixture was stirred at room temperature (RT) for
60 min, which afforded 74% of the desired product as a white solid (Table 1, entry 10).
1
The structure of 4a is assigned with the help of H NMR and 13C NMR data. Further,
the same reaction has been studied with different solvents like methanol, acetonitrile,
dimethylformamide, toluene and tetrahydrofuran at RT, resulting in the desired product
in moderate (40–72%) yield (Table 1, Entries 11–17). Screened different catalysts for
this reaction, such as Cu(OTf)2 (20%), InCl3 (20%), L-proline (20%), Piperidine (20%),
FeCl3 (20%), p-TsOH (20%), Sc(OTf)3 (20%), GaCl3 (20%) and InBr3 (20%) (Table 1,
Entries 1–9). All screened catalysts were found to be effective for this conversion.
However, when the reaction is carried out with PEG-600, the viscosity of the reaction
mixture is increased highly at RT and the reaction gets stuck, hence the reactants do
not interact effectively. The expected product is obtained a yield of 60% in 60 min
(Table 1, Entry 17). However, the reaction rate increased when the solvent was switched
from PEG-600 to PEG-600: EtOH. Therefore, the volumetric ratio of PEG and EtOH
was screened and the best results were obtained by carrying out the reaction in PEG-
600: EtOH with a ratio of 1:1(v/v) (Table 1, Entry 20).
When used PEG-600 and EtOH as an eco-friendly reaction medium, the reaction
gave an excellent result (96% yield) within 20 min at the ambient temperature. It has
been found that the reaction proceeded very well with increased yields, which clearly
indicates that the PEG-600 is the most effective reaction medium and promoter for this
transformation. From the results depicted in Table 1, we have selected the PEG-600 and
ethanol as a suitable reaction medium due to highest yield, in shorter reaction time,
and environmentally favorable.
Using these optimized reaction conditions, the generality of this reaction is being
verified using different aromatic amines with various substitutes are reacted successfully
by bearing electron-donating (such as methyl, methoxy) as well as electron-withdrawing
(such as halide) substituents. The reaction proceeded more quickly with aniline contain-
ing electron-donating groups (–Me, –OMe) to give the products in excellent yields
(4d–4i) within 15–45 min. The steric and electronic properties of the substituted amine
had very little impact on the efficiency of this reaction. However, when 1,4-phenylenedi-
amine with formaldehyde, and 4-hydroxyquinolin-2(1H)-one were used, gave the
desired product 3,30-(1,4-phenylene)bis(3,4-dihydro-2H-[1,3]oxazino[5,6-c]quinolin-
5(6H)-one) 4p was obtained in 78% yield. Similarly, the reaction of 4-hydroxy-1-meth-
ylquinolin-2(1H)-one with formaldehyde and aniline were used, gave the desired
product 3,4-dihydro-6-methyl-3-phenyl-2H-[1,3]Oxazino[5,6-c] quinolin-5(6H)-one 4aa
was obtained in 94% yield. Unfortunately, aromatic amine with methoxy at 3 position
or 3,5 dimethoxy substituted aromatic amine could not react with formaldehyde and 4-
hydroxyquinolin-2(1H)-one to give the desired product (4q, 4r). On the other hand,
short-chain aliphatic amine such as 3-methoxypropan-1-amine did not react under the
optimized reaction condition (4s).
The reaction of 4-methylumbelliferone (5a, 1 mmol), formaldehyde (2a, 3 mmol, 37%
aqueous solution), aniline (1a, 1.2 mmol) was carried out in PEG-600: EtOH (1:1, v/v)
at 80 ꢁC for 3 h. A study of the effect of temperature on the reaction time as well as on
the yield of the product reveals that the reaction is strongly influenced by the tempera-
ture. These results are presented in Table 2.

4
M. B. YADAV ET AL.
NH2
OH
O
N
O
R
O
PEG+EtOH (1:1)
rt, 15-45 min
+
+
H
H
N
X
O
N
X
R
2a
1a
3a
X= H,CH3
(4a-4p, 4aa)
Scheme 2. Synthesis of [1,3]Oxazino quinoline derivatives (4a–4p, 4aa)a,b
.
aReaction conditions: 4-hydroxyquinoline (1 mmol, 3a), formaldehyde (3 mmol, 37% aqueous solution,
b
2a), aromatic amine (1.2mmol, 1a), and solvent 4 mL at room temperatures. Isolated yield.

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5
Table 1. Optimization of reaction conditionsa.
Entry
Promoter (mol. %)
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
Cu(OTf)2 (20)
InCl3 (20)
L-proline (20)
Piperidine (20)
FeCl3 (20)
p-TsOH (20)
Sc(OTf)3 (20)
GaCl3 (20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
CH3CN
DMF
DMSO
Toluene
THF
PEG
PEG: EtOH(1:5)
PEG: EtOH(1:3)
PEG: EtOH(1:1)
60
60
60
60
60
60
60
60
60
82
77
80
79
82
85
75
78
77
74
45
40
72
38
42
72
60
81
89
96
9
InBr3 (20)
10
11
12
13
14
15
16
17
18
19
20
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
Catalyst-free
60
360
360
60
360
360
60
60
30
30
30
aReaction conditions: 4-hydroxyquinolin-2(1H)-one (1 mmol, 3a), formaldehyde (3 mmol, 37% aqueous solution, 2a), anil-
ine (1.2 mmol, 1a), and solvent 4 mL at room temperature. bYield.
Table 2. Effect of temperaturea,b
.
Entry
Solvent
Temperature (ꢁC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
EtOH
EtOH
RT
80
RT
40
60
80
80
80
80
80
12
12
12
12
12
12
6
4
3
1
0
52
0
EtOH:PEG
EtOH:PEG
EtOH:PEG
EtOH:PEG
EtOH:PEG
EtOH:PEG
EtOH:PEG
EtOH:PEG
0
58
93
94
91
90
63
aReaction conditions: 4-methylumbelliferone (1 mmol, 5a), formaldehyde (3 mmol, 37% aqueous solution, 2a), aniline
(1.2 mmol, 1a), and solvent 4 mL stirred at different temperatures. bIsolated yield.

6
M. B. YADAV ET AL.
When the reaction is being carried out under room temperature, the desired product
could not be observed, as the starting materials were unreactive (Table 2, Entry 1). The
results of screening temperature (Table 2) reveals that 80 ꢁC would be the optimal tem-
perature, at which the reaction proceeds rapidly and produces the best yield 90% (Table 2,
Entry 9) in 3 h. Further verified reaction time does not cause any significant change in the
1
product yield. The structure of 6a is assigned with the help of H NMR and 13C NMR
data. We have also employed various substituted aromatic amine with electron-donating
substituents such as –Me, –OMe, and halogen (Br) which were well tolerated and provided
the corresponding products in good to excellent yields. However, p-nitro aniline did not
afford the desired product under the optimized reaction conditions (Scheme 3, 6i).
After having successfully developed a one-pot strategy for the construction of 3-phe-
nyl-3,4-dihydro-2H-[1,3]oxazino[5,6-c]quinolin-5(6H)-one, we examined the synthetic
utility of this reaction. Consequently, we performed the reaction on a gram-scale
(10 mmol, 1.60 g) under the standard reaction conditions and isolated desired product
4a in 90% yield (Scheme 4).
We have proposed a plausible reaction mechanism (Fig. 1). Initially, aniline (1a)
reacts with formaldehyde (2a) to form Schiff base A by Mannich type condensation, 4-
hydroxyquinolin-2(1H)-one (3a) undergoes nucleophilic addition with A to form inter-
mediate B. Next, the intermediate B reacts with second molecule of formaldehyde (2a)
to afford the intermediate C. Then intermediate C undergoes intramolecular cyclization
followed by water elimination to afford the desire product [1,3] Oxazino[5,6-c] quin-
oline-5-one (4a). The results from all the above studies clearly indicate, that the present
non-catalytic protocol is compatible for a wide range of substrates to construct a diver-
sity-oriented library of 1,3-Oxazino quinoline and chromeno 1,3-oxazin derivatives.
Conclusion
In summary, we have developed a convergent and robust greener protocol for the
synthesis of 1,3-Oxazino quinoline and chromeno 1,3-oxazin derivatives by the three-
component reaction of various aromatic amines with formaldehyde and 4-hydroxyqui-
noline-2(1H)-one or 4-methylumbelliferone by using PEG-600: EtOH as an effective
reaction medium under catalyst free-conditions. The simple straightforward, rapid,
atom-economic, high yielding, as well as inexpensive and eco-friendly nature, are the
key benefits of this method, which constitutes an attractive tool addressing the access to
1,3-oxazine molecules for bioactive applications.
Experimental
Materials
Chemical were purchased from Sigma Aldrich and Alfa Aesar chemical companies and
used without further purification. NMR spectra were recorded in parts per million
(ppm) in DMSO-d6 and Chloroform-d on a Jeol JNM ECP 400 NMR instrument using
TMS as internal standard abbreviation were used to denoted signals multiplicities
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplate). HRMS were obtained
by EI on a double-focusing mass analyzer, ESI (positive ion mode) on TOF mass

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Scheme 3. Synthesis of chromeno 1,3-oxazin derivatives (6a–6i)a,b
aReaction conditions: 4-methylumbelliferone (1 mmol, 5a), formaldehyde (3 mmol, 37% aqueous solu-
b
tion, 2a), aromatic amine (1.2 mmol, 1a), and solvent 4 mL stirred at 80 ꢁC for 3 h. Isolated yield.
analyzer. All melting points were determined using open capillaries on an Electro ther-
mal-9100(Japan) instrument and are uncorrected.
General procedure
General procedure for synthesis of [1,3]oxazino quinoline derivatives (4a)
A mixture of 4-hydroxyquinoline-2(1H)-one (3a, 1 mmol), aniline (1a, 1.2 mmol) and for-
maldehyde (2a, 3 mmol 37% aqueous solution) in 4 mL of PEG-600 and EtOH (V/V, 1:1)

8
M. B. YADAV ET AL.
Scheme 4. Gram scale reaction.
Figure 1. A plausible mechanism for the [1,3]Oxazino [5,6-c]quinoline-5-one.
was magnetically stirred at room temperature for 15–45min. Reaction was monitored by
thin-layer chromatography (eluent: 60% ethyl acetate/hexane, Rf ¼ 0.60). After completion
of the reaction, solid products was filtered under vacuum, air dried, to obtain the analytically
pure products. The compounds 4a–4p and 4aa were also synthesized by adopting
this procedure.
It was obtained as white solid; Yield: 96%; MP:198–200 ꢁC; 1H NMR (400 MHz,
DMSO-d6) d 11.53 (s, 1H), 7.68 (d, J ¼ 8.1 Hz, 1H), 7.48 (t, J ¼ 8.4 Hz, 1H), 7.26 (dd,
J ¼ 13.9, 7.4 Hz, 3H), 7.15 (dd, J ¼ 8.4, 1.3 Hz, 3H), 6.90 (t, J ¼ 7.3 Hz, 1H), 5.66 (s, 2H),
4.38 (s, 2H); 13C NMR (100 MHz, DMSO-d6) d 161.89, 157.85, 148.24, 137.94, 136.05,
130.98, 129.77, 122.84, 121.06, 118.29, 115.83, 114.30, 106.04, 80.69, 45.73; HRMS (ESI,
m/z): calcd. for C17H14N2O2 (M þ Hþ) 278.1055, found: 279.1057.

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9
General procedure for gram scale reaction (4a)
A mixture of 4-hydroxyquinoline-2(1H)-one (3a, 10 mmol), aniline (1a, 12 mmol) and
formaldehyde (2a, 30 mmol 37% aqueous solution) in 12 mL of PEG-600 and EtOH (V/
V, 1:1) was magnetically stirred at room temperature for 30 min. Reaction was moni-
tored by thin-layer chromatography. After completion of the reaction, solid product was
filtered under vacuum, air dried, to obtain the analytically pure products.
General procedure for synthesis 4-methyl-9-phenylchromeno [8,7-e][1,3]oxazin-2(8H)-
one (6a)
A mixture of 4-Methylumbelliferone (5a, 1 mmol), aniline (1a, 1.2 mmol) and formalde-
hyde (2a, 3 mmol 37% aqueous solution) in 4 mL of PEG-600 and EtOH (V/V, 1:1) was
magnetically stirred at 80 ꢁC for 3 h. Reaction was monitored by thin layer chromatog-
raphy (eluent: 5% methanol/dichloromethane, Rf ¼ 0.40). As the reaction mixture
cooled, the raw product precipitate in to white-yellow crystals. Finally, recrystallization
from toluene yielded white needle like crystals. The compounds 6a–6h were also synthe-
sized by adopting this procedure.
It was obtained as white solid; Yield: 90%; MP:148–150 ꢁC; 1H NMR (400 MHz,
CDCl3) d 7.37 (d, J ¼ 8.8 Hz, 1H), 7.28 (dd, J ¼ 9.6, 6.4 Hz, 2H), 7.15 (d, J ¼ 7.7 Hz, 2H),
6.96 (t, J ¼ 7.3 Hz, 1H), 6.78 (d, J ¼ 8.8 Hz, 1H), 6.13 (s, 1H), 5.44 (s, 2H), 4.83 (s, 2H),
2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) d 161.29, 157.82, 153.38, 151.44, 148.18,
129.67, 123.86, 122.30, 118.79, 113.91, 113.55, 111.98, 109.13, 80.11, 46.58, 19.02; HRMS
(ESI, m/z): calcd. for C18H15NO3 (M þ Hþ) 293.1052, found: 294.1052.
1
Experimental details, H and 13C NMR spectra have been provided in supporting
information.
Funding
This work was supported by a research grant of Pukyong National University (2019).
ORCID
Yeon Tae Jeong
http://orcid.org/0000-0002-2943-6954
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