Catalyst free synthesis of 2-Aryl-2H-benzo[b][1,4]oxazines and 3-Aryl-2H-benzo[b][1,4]thiazin-2-ones: An ultrasonication-assisted strategy

Article abstract of DOI:10.1002/jhet.4267

An ultrasonication-assisted synthesis of 2-Aryl-2H-benzo[b][1,4]oxazines and 3-aryl-2H-benzo[b][1,4]thiazin-2-ones has been established by reacting phenacyl bromides with 2-aminophenol and 2-aminothiophenol, respectively. This approach fosters flexibility in generating a diverse range of 1,4-benzoxazines and 1,4-benzothiazinones under catalyst-free reaction conditions. Further scope toward the synthesis of rarely occurring bis-benzoxazine adduct has also been explored, which enabled us to propose the reaction mechanism.

Full text of DOI:10.1002/jhet.4267

Received: 1 February 2021
DOI: 10.1002/jhet.4267
Revised: 9 March 2021
Accepted: 16 March 2021
C O M M U N I C A T I O N S
Catalyst free synthesis of 2-Aryl-2H-benzo[b][1,4]oxazines
and 3-Aryl-2H-benzo[b][1,4]thiazin-2-ones: An
ultrasonication-assisted strategy
Bisma Teli1,2 | Malik Abdul Waseem1 | Showkat Rashid1
Bilal Ahmad Ganaie1 | Bilal A. Bhat1,2
|
1Natural Products and Medicinal
Abstract
Chemistry, CSIR-Indian Institute of
Integrative Medicine, Jammu & Kashmir,
India
2Academy of Scientific & Innovative
Research (AcSIR), Ghaziabad, India
An ultrasonication-assisted synthesis of 2-Aryl-2H-benzo[b][1,4]oxazines and
3-aryl-2H-benzo[b][1,4]thiazin-2-ones has been established by reacting phen-
acyl bromides with 2-aminophenol and 2-aminothiophenol, respectively. This
approach fosters flexibility in generating a diverse range of 1,4-benzoxazines
and 1,4-benzothiazinones under catalyst-free reaction conditions. Further
scope toward the synthesis of rarely occurring bis-benzoxazine adduct has also
been explored, which enabled us to propose the reaction mechanism.
Correspondence
Bilal A. Bhat, Natural Products and
Medicinal Chemistry, CSIR-Indian
Institute of Integrative Medicine,
Jammu & Kashmir 190005, India.
Email: bilal@iiim.res.in
Funding information
SERB, India, Grant/Award Number:
CRG/2019/005179; IIIM communication
No. Grant/Award Number: CSIR-IIIM/
IPR/00281
1 | INTRODUCTION
and Escherichia coli M17 is based on a benzothiazinone
scaffold[10] (Figure 1).
1,4-Benzoxazine motif constitutes an intrinsic part of a
large class of heterocyclic constructs with a cosmopolitan
distribution in drugs, bioactive agents, and a wide range
of natural products.[1–4] Antibiotic drug, levofloxacin,[5]
serotonin 3 receptor antagonist, azasetron,[6] neuro-
protective synthetic compound HSB-13[7] and natural
products like pitucamycin and dandamycin[8] are some of
the commonly encountered examples harboring this
important structural construct. A rare tetracyclic natural
product based on bis-benzoxazine motif was also recently
isolated from a co-culture of sponge-associated actinomy-
cetes.[9] Similarly, benzothiazinones also constitute an
essential heterocyclic motif present in a large number of
bioactive compounds. For example, a bacteriostatic agent
exhibiting activity against Staphylococcus aureus P-209
Keeping into consideration the ubiquitous nature of
1,4-benzoxazines and their wide range of biological
activities,[1–9] an ample number of synthetic methods
have been developed toward this end. Traditional syn-
thesis of 1,4-benzoxazine derivatives involves multistep
processes, using 2-nitrophenols or 2-aminophenols as
the starting materials.[11] However, due to their grow-
ing canvas, 1,4-benzoxazine derivatives have prompted
newer and more efficient methodologies that follow
diverse one-pot strategies including metal-catalyzed
reactions,[12–20] cascade reactions[21–25] or even
microwave-assisted transformations.[26,27] Toward the
synthesis of 2-aryl-1,4-benzoxazines, recently two gen-
eral strategies emerged in the literature (Scheme 1).
One involves the oxidative dearomatization of quinols
with amino acid derivatives[28] and the another one is
based on BF3-mediated Friedel Crafts arylation
Bisma Teli and Malik Abdul Waseem equally contributed to this work.
J Heterocyclic Chem. 2021;1–5.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

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TELI ET AL.
2-aryl-1,4-benzoxazine was obtained as an exclusive prod-
uct. This protocol was further elaborated on a range of
substrates and also modified to demonstrate its applica-
tion toward bis-benzoxazine derivatives. It is pertinent to
mention that under acidic or basic conditions, the reac-
tion between 2-aminophenol and phenacyl bromide or
chloride is reported to change its path completely and
furnish 3-aryl,1-4-benzoxazine as the main prod-
uct[24,33,34] (Scheme 1).
Initially, we began our study with the reaction of
2-aminophenol (1) and phenacyl bromide (2) under vari-
ous reaction conditions at variable temperatures in differ-
ent organic solvents (Table 1). Our results indicated that
this reaction was sluggishly working in various protic
and aprotic solvents (entry 1–4). However, in a polar sol-
vent like DMSO, and non-polar solvent like hexane, this
reaction was not working at all (entry 5 and 8). There-
fore, we sought to attempt it in chlorinated solvents like
dichloromethane and chloroform, but the reaction was
highly sluggish (entry 6 & 7). However, it was encourag-
ing to see a decent conversion of the reaction in THF at
rt or 60ꢀC (entry 9 & 10). By switching over to ultrasonic
conditions (40 kHz) at 60ꢀC in THF as a solvent, we were
delighted to see the complete conversion of reactants
within an interval of 2 h and the product was obtained in
a decent yield (entry 11). Based on these results, the reac-
tion was further attempted in 1,4-dioxane at rt, but under
these conditions, it was not effective like in most other
solvents (entry 12). Therefore, the reaction was found
comparatively suitable in THF at 60ꢀC under sonication
conditions (Table 1).
FIGURE 1 1,4-benzoxazine-based drugs, bioactive entities,
natural products, and benzothiazinone agent
To examine the generality and scope of this method,
several phenacyl bromide derivatives having electron-
donating and withdrawing groups, halogenated, hetero-
cycle, and biphenyl compounds were used in this study
to increase the substrate scope. We initially tested this
reaction on compounds having electron donating groups.
It was observed that the reaction proceeded smoothly to
furnish the products 4 and 5 as in case of product
3 (Table 2). In case of compounds having halogen substi-
tution, the reaction was slightly better than compounds
with electron donating groups. However, in case of
compounds with electron-withdrawing group attached to
the ring-B, the reaction was somewhat efficient than the
earlier two cases. We next sought to further broaden its
canvas on ring-A substituted compounds and
2-aminothiophenol compounds. Due to their limited
commercial availability, we used the 3-nitro-aminophenol
and phenacyl bromide initially. It was interesting to
observe that the reaction between 3-nitro-2-aminophenol
and phenacyl bromide furnished 3-aryl-benzoxazine as an
exclusive product instead of 2-aryl-benzoxazine. The rea-
son could be attributed to the possible electronic effects,
SCHEME 1 General approaches to access 2-aryl
1,4-benzoxazines
reaction of 1-hydroxy-1,4-benzoxazines.[29] Despite
accounting for some interesting chemical reactions,
both the strategies are not free from limitations in
terms of substrate scope.
As a part of our ongoing medicinal chemistry
research program on heterocyclic bioactive entities,[30–32]
a research endeavor was initiated to establish a flexible
protocol for synthesizing 1,4-benzoxazine derivatives.
Keeping in mind the acidic and basic functional groups
attached to 2-aminophenol, we subjected it to react with
phenacyl bromide under ultrasonication condition,

TELI ET AL.
3
TABLE 1 Optimization of reaction conditions for the synthesis of 2-aryl-1,4-benzoxazines
Entry
Solventa
MeOH
EtOH
Condition
Time, h
%Yield 3b
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
6
6
6
6
6
6
6
6
6
5
2
32
30
35
20
0
2
3
EtOH: H2O
MeCN
DMSO
CH2Cl2
CHCl3
Hexane
THF
4
5
6
20
20
0
7
8
9
50
45
60
10
11
THF
THF
sonication
(60ꢀC, 40 kHz)
12
1,4-Dioxane
rt
6
15
aAll the reactions were attempted at 1 mmol scale in 10 ml of solvents.
bIsolated yield.
TABLE 2 Access to substituted 2-aryl-1,4-benzoxazinesa
the powerful electron-withdrawing nitro group at
position-3 in 3-nitro-aminophenol diminishes the electron
density at 2-amino group and thereby the first attack takes
place through -OH group (discussed vide infra in mecha-
nism). Further, the reaction was also tried on thiophene
and biphenyls substituted compounds (12 and 13). To our
delight, this reaction also worked well in all these cases,
irrespective of the position and substitutions (Table 2).
After the reaction was found successful on a range of
1,2-aminophenols, we next sought to broaden its canvas
on 1,2-aminothiophenols under similar conditions. Inter-
estingly, the reaction of 1,2-aminothiophenol with phen-
acyl bromide under sonication in the presence of air lead
to the aromatic ring swapping and result in the formation
of 3-phenyl-2H-benzo[b][1,4]thiazin-2-one as an exclu-
sive product (Table 3). It is pertinent to mention that this
product was earlier accessed in two steps involving one
additional oxidation-step using similar starting mate-
rials.[35,36] Since our protocol leads an in-situ air oxida-
tion therefore, we tested it on a range of different
substrates having electron-donating, withdrawing groups
and halogen substitutions. As is evident from Table 3 the
compounds 15–20 were obtained in excellent yields.
Having addressed its generality and substrate scope,
we next attempted to utilize this reaction further toward
bis-benzoxazines. In this endeavor, we first reacted com-
pound 3 with another mole of 2-aminophenol to establish

4
TELI ET AL.
TABLE 3 Access to substituted 3-aryl-2H-benzo[b][1,4]
Based on these results, we tried to explain the plausi-
ble mechanism for the formation of 2-aryl-1,-
4-benzoxazines, 3-aryl-2H-benzo[b][1,4]thiazin-2-one and
bis-benzoxazine adducts. We propose that in the presence
of acid or base as reported in earlier methods, the first
attack of 2-aminophenol takes place through oxygen
functionality due to the more nucleophilic character of
phenoxide ion than ammonium ion. As a result, 3-aryl-1,-
4-benzoxazines were the only products obtained in litera-
ture so far. However, under neutral conditions, as
expected, NH2 group is more nucleophilic and therefore
undergoes N-alkylation with phenacyl bromide to furnish
the intermediate I (Scheme 3). Cyclization of the inter-
mediate I takes place through phenol group addition on
carbonyl group, followed by eliminating water to result
in intermediate II. Double bond repositioning in interme-
diate II furnished the product 3. This compound, when
treated with another mole of 2-aminophenol, a rare pen-
tacyclic bis-benzoxazine adduct, 21, was formed possibly
through the intermediacy of oxycarbonium ion III. This
oxycarbonium ion is formed under the influence of
2-aminophenol and is stabilized due to benzylic, allylic
groups and also due to oxycarbonium ion effects. In case
of 3-aryl-2H-benzo[b][1,4]thiazin-2-ones, phencyl bro-
mide undergoes –SH alkylation with thiol group to inter-
mediate IV followed by cyclization (to V) and water
elimination to intermediate VI. In situ air oxidation of
the intermediate VI under the reaction conditions leads
to compound 15 as an exclusive product.
thiazin-2-one
SCHEME 2 Applications toward the synthesis of bis-
benzoxazines
its reactivity and mechanism. Under similar reaction con-
ditions in 24 h, this compound was converted to bis-
benzoxazine derivatives (21) albeit in compromised yield
(Scheme 2). Later on, we concluded that when the reac-
tion of phenacyl bromide (1 mole) was carried out with
2-moles of aminophenol, bis-benzoxazine derivative (21)
was again obtained as one of the products (Scheme 2).
The structure and stereochemistry of compound 21 were
assigned unambiguously through a single X-ray crystal
structure analysis. It is to note that these bis-benzoxazine
regiomers are present in recently isolated and rarely
occurring bioactive natural products isolated from the co-
culture of sponge-associated actinomycetes.[9]
SCHEME 3 Plausible mechanism of formation of 2-aryl-
1,4-benzoxazines and bis-benzoxazine adducts

TELI ET AL.
5
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2 | CONCLUSIONS
In conclusion, we established a new strategy to synthe-
size 2-aryl-1,4-benzoxazines and 3-aryl-2H-benzo[b][1,4]
thiazin-2-one under ultrasonication conditions without
the involvement of any catalyst. Its scope was demon-
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stitutions and functionalities. We also elaborated its
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Bisma Teli and Malik Abdul Waseem wish to acknowl-
edge the Science and Engineering Research Board
(SERB)-India for financial support through fellowship
grants. Bilal Ahmad Ganaie acknowledges the CSIR-IIIM
Srinagar for hosting him as a PhD trainee. Bilal A. Bhat
acknowledges the grant support of SERB, India
(CRG/2019/005179; IIIM communication No. CSIR-IIIM/
IPR/00281).
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Supporting data is available
ORCID
Bilal A. Bhat https://orcid.org/0000-0002-0239-7625
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How to cite this article: Teli B, Waseem MA,
Rashid S, Ganaie BA, Bhat BA. Catalyst free
synthesis of 2-Aryl-2H-benzo[b][1,4]oxazines and
3-Aryl-2H-benzo[b][1,4]thiazin-2-ones: An
ultrasonication-assisted strategy. J Heterocyclic
Chem. 2021;1–5. https://doi.org/10.1002/jhet.4267