Synthesis of 4H-chromene-isoxazole hybrids via ortho-hydroxy directing cyclization of isoxazole-styrenes and Michael addition of imino-chromenes in aqueous medium

Article abstract of DOI:10.1002/jhet.4251

A green, efficient, and one-pot method synthesis of functionalized 4H-chromene-isoxazole hybrids is reported via o-hydroxy group directing cyclization of isoxazole-styrenes and Michael addition of 3,5-dimethyl-4-nitroisoxazole on 2-imino-2H-chromene-3-carbonitrile (independent methods). The developed methodology was further extended for nitromethane, malononitrile, and alkylcyanoacetates as Michael donors.

Full text of DOI:10.1002/jhet.4251

Received: 16 October 2020
DOI: 10.1002/jhet.4251
Revised: 18 January 2021
Accepted: 15 February 2021
A R T I C L E
Synthesis of 4H-chromene-isoxazole hybrids via
ortho-hydroxy directing cyclization of isoxazole-styrenes and
Michael addition of imino-chromenes in aqueous medium
Sakkani Nagaraju | Kota Sathish | Dhurke Kashinath
Department of Chemistry, National
Abstract
Institute of Technology, Warangal, India
A green, efficient, and one-pot method synthesis of functionalized 4H-chromene-
Correspondence
Dhurke Kashinath, Department of
isoxazole hybrids is reported via o-hydroxy group directing cyclization of isoxazole-
styrenes and Michael addition of 3,5-dimethyl-4-nitroisoxazole on 2-imino-2H-
Chemistry, National Institute of
Technology, Warangal 506 004, India.
chromene-3-carbonitrile (independent methods). The developed methodology was
Email: kashinath@nitw.ac.in; kashinath.
further extended for nitromethane, malononitrile, and alkylcyanoacetates as
dhurke@gmail.com
Michael donors.
Funding information
Science and Engineering Research Board,
Grant/Award Numbers: SB/EMEQ-
103/2014, SB/FT/CS-136/2012
1 | INTRODUCTION
perfumes, and cosmetics. Especially, the coumarin-
4-carboxymethyl compound and its derivatives are used as
dye-sensitized solar cells, in fluorogenic assay for the detec-
tion of β-D-glucosidase, fluorescent probes, and organ-
ogelators [5]. The preparation of 2-amino-3-cyano-4H-
chromenes using salicylaldehydes is known method
through multicomponent reactions which are economic,
time-saving with simple operation and separation tech-
niques. Due to this, one-pot reactions got attention in aca-
demic and industrial research [6a], [6b]. 2-Amino-3-cyano-
4H-chromenes can also be prepared from aromatic unsatu-
rated compounds using multicomponent approach [6c–h].
The isoxazole is an important heterocyclic compound
seen in many natural, and synthetic drugs such as
AMPA, Ibotenic acid [1], cloxacillin (antibiotic), isoxicam
(NSAID), leflunomide (immunosuppressive agent),
muscimol (GABA agonist), and COX-2 inhibitors. The
synthetic derivatives of isoxazoles are known to show
insecticidal, antibacterial, antibiotic, antitumor, antifun-
gal, anti-tubercular, ulcerogenic properties and used as
inhibitors of heat shock protein 90 activity (Hsp 90), initi-
ators of neurogenesis [1,2].
Chromene scaffold found in tocopherols, flavonoids,
anthocyanins, medicinally important compounds and con-
sidered as privileged structures [3]. 2-Amino-3-nitrile-4H-
chromenes known as anticancer agents (tubulin-binding),
antagonists for anti-apoptotic Bcl-2 proteins, apoptosis-
inducing agents, and antagonists for excitatory amino acid
transporter subtype-1. In addition to these, 4H-chromenes
are part of marketed drugs used for asthma, hypertension,
ischemia, urinary incontinence, and used in pigments, cos-
metic, and agrochemical industries [4]. Coumarins are iso-
meric structures of chromenes present in wide range of
biologically active molecules. The substituted coumarins at
position 4 are used as drugs for tuberculosis, HIV, pesticides,
3-Methyl-4-nitro-5-styrylisoxazole is known as a
masked ester for the generation of carboxylic acid [7a].
Also, the methyl group present at position 3 has been
used in Knoevenagel, Aldol, Michael, and cycloaddition
reactions [7]. However, the formation of two new bonds
with Michael addition followed by a neighboring group
directed cycloaddition/Pinner type reaction is not yet
explored in the literature. Also, there are no reports of
C C, C O bond formation followed by annulation and
isomerization (Pinner type reaction) in an intramolecular
fashion. Owing to the biological importance of isoxazoles,
4H-chromenes [4], coumarins [5], and in continuation of
our efforts in developing new synthetic methods under
J Heterocyclic Chem. 2021;1–7.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

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NAGARAJU ET AL.
green conditions (“on-water” concept) [8], [9], herein, we
report the synthesis of functionalized isoxazole-
chromene/coumarin hybrids using o-hydroxy directing
cyclization and Michael addition reactions as a key step.
in the presence of Et3N (30 mol%) in ethanol to give
1,6-Michael adduct (3) with 63% yield (Scheme 1). Simi-
larly, a reaction was attempted using 2-hydroxy-iso-
xazole-styrene (4) with malononitrile (1) in the presence
of Et3N (30 mol%) to give 4H-chromene-isoxazole hybrid
(5) with 75% yield (Scheme 1). These observations
prompted us to explore the role of OH group at ortho
position to unsaturated bond and isoxazole for the cycli-
zation under similar conditions. Therefore, it was decided
to adopt a one-pot approach for the synthesis of the 4H-
2 | RESULTS AND DISCUSSION
Towards the synthesis 4H-chromene-isoxazole hybrids,
isoxazole-styrene (2) was reacted with malononitrile (1)
SCHEME 1 1,6-Michael addition reaction of malononitrile (1) and isoxazole styrenes (2 and 4)
TABLE 1 Optimization of the conditions for synthesis of product 5 in one pot method
S. No.
1
Solvent (2 mL)
CH3CN
DMF
Catalyst (30 mol%)
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
Reaction time (h)
Yield (%)a
Trace
Trace
Trace
10
24
24
24
24
24
24
24
24
24
24
24
24
24
06
02
02
2
3
DMSO
MeOH
EtOH
4
5
25
6
CH3CN
MeOH
EtOH
Trace
30
7
DBU
8
DBU
67
9
Water
DBU
70
10
11
12
13
14
15
16
MeOH
EtOH
TEA
25
TEA
45
Water
TEA
50
CH3CN
MeOH
EtOH
Piperidine
Piperidine
Piperidine
Piperidine
30
70
93
Water
95
Note: All of the reactions were performed with 1 mmol scale at 65ꢀC.
aIsolated yields. Bold values indicates the best results.

NAGARAJU ET AL.
3
chromene-isoxazole hybrids. Thus, the styrene (4) was
generated in situ by the reaction of salicylaldehyde (6)
and 3,5-dimethyl-4-nitroisoxazole (7) and treated with
malononitrile (1) to give the cyclized product (5) with
45% yield (Table 1; Entry-11).
donor). To achieve this, 2-imino-2H-chromene-
3-carbonitrile (8) [prepared from salicylaldehyde and
malononitrile] [10a] was reacted with 3,5-dimethyl-
4-nitroisoxazole (7) in the presence of Et3N (30 mol%) in
EtOH to give the desired compound (5) in 70% yield
(Scheme 2). Based on these observations, an attempt for a
catalyst-free reaction of salicylaldehyde (6), malononitrile
(1) in water at 60–80ꢀC gave an imine in quantitative
yield (99%, TLC conversion) for 30 min. To this (same
reaction pot), 3,5-dimethyl-4-nitro-isoxazole (7) was
added and heating continued for another 3 h to give the
desired 4H-chromene-isoxazole hybrid (5) in 94% yield.
To compare the efficiency of these results, the same reac-
tion was performed for different concentrations of water
and other solvents (polar aprotic and protic), brine, and
D2O. These experiments indicate that the water at 0.5 M
concentration is ideal condition for obtaining best yield
(94%; Table 2, Entry-4) and support “on-water” concept
for the success of the reaction.
With the aim of improving yields, experiments were
performed in the presence of different bases
[1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU), TEA, and piperidine] and sol-
vents (aprotic polar, and protic) as indicated in (Table 1).
From these studies, it is observed that the bases DABCO,
DBU, and TEA are not much effective for the generation
of the intermediate (4). However, piperidine (30 mol%)
gave desired product with 93%–95% yield in protic sol-
vents (EtOH and water) for 2 h at 65ꢀC temperature.
A simultaneous strategy for the synthesis of com-
pound 5 was envisaged based on Michael addition reac-
tion of 2-imino-2H-chromene-3-carbonitrile (as Michael
acceptor) and 3,5-dimethyl-4-nitroisoxazole (as Michael
Having the reaction conditions in hand, toward the
generalization and to check the subsrate scope in both
the methods, different salicylaldehydes (6b-6h) were
treated with 3,5-dimethyl-4-nitro-isoxazole (7) to gener-
ate isoxazole-styrenes (4; in situ). The compound was
then reacted with malononitrile/methyl cyanoacetate/
ethyl cyanoacetate to give 4H-chromene-isoxazole
hybrids (5a-5r) in 85%–95% yields (Method A in
Figure 1). Similarly, the iminochromenes (8) [generated
SCHEME 2 Synthesis of isoxazole-4H-chromene hybrids (5a)
via Michael addition reaction of nitroisoxazole (7) and 2-imino-2H-
chromene-3-carbonitrile (8)
TABLE 2 Optimization of the conditions for synthesis of 5 (one-pot method and catalyst-free condition)
S. No.
Solvent (2 mL)
MeOH
Temp (ꢀC)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
60
60
80
80
80
80
80
80
80
24
24
6
55
65
72
94
84
85
80
50
20
EtOH
Water
Water (0.5 M)
Water (4 mL) (0.25 M)
Water (3 mL) (0.33 M)
Water (1 mL) (1 M)
Brine
03
06
06
06
24
24
D2O
Note: All of the reactions were performed with 1 mmol scale.
aIsolated yields. Bold values indicates the best results.

4
NAGARAJU ET AL.
FIGURE 1 Substrate scope for the 4H-chromene-isoxazole hybrids (5a-5r) using method-A, and method-B

NAGARAJU ET AL.
5
by the reaction of salicylaldehydes and malononitrile/
methyl cyanoacetate/ethyl cyanoacetate at 80ꢀC in water
(catalyst-free)] on treatment with 3,5-dimethyl-4-nitro-
isoxazole (7) gave 4H-chromene-isoxazole hybrids (5a-5r)
in 84%–96% yields (Method B in Figure 1).
As mentioned in the introduction, coumarin acetic
acids are important molecules in medicinal chemistry
and can be used as fluorescent molecules [5]. The
nitroisoxazole moiety is known as carboxylic acid equiva-
lent [7a]. Also, it is known that the 2-aminochromenes
can be converted into coumarins [11]. Considering this,
the 4H-chromene-isoxazole (5) was reacted with known
reagents [11] as indicated in Table 3. All the reagents
could give the desired product. But, iodine was found to
be better in a combination of tBuOH + H2O as a reaction
medium giving the desired isoxazole-coumarin (13a-13e)
up to 96% yield (Scheme 4). The plausible mechanism for
this transformation is given in the Supporting
Information (Figure S3). Further, the isoxazole-coumarin
(13d) was treated for iosaxazole ring opening to give
2-(6-chloro-3-cyano-2-oxo-2H-chromen-4-yl)acetic acid
14. Similarly, the chromene-isoxazole amine 15 was
obtained (in 93%) by nitro reduction of 5m by treating in
the presence of Zn powder in acetic acid for 1 h
(Scheme 5).
After synthesizing the 4H-chromene-isoxazole
hybrids (5a-5r), we have decided to apply this method for
the nitromethane as a nucleophile. Thus, the imines
[generated from salicylaldehydes (6) and malononitrile
(1)] were treated with nitromethane (9) under optimized
conditions (catalyst-free) using water as reaction medium
to give the desired 2-amino-4-(nitromethyl)-4H-
chromene-3-carbonitriles (10a-10e) with good yields
(86%–91%) for 30 min at 80ꢀC (Scheme 3). Further to
increase the complexity, the iminochromenes were also
reacted with malononitrile (1 equiv and 2 equiv) under
optimized conditions. It is noteworthy to mention that
the stoichiometry of the malononitrile play an important
role to give the expected Michael adducts (11a-11e) and
chromene-pyridine hybrids (12a-12c) with good yields
(Scheme 3). These results can be comparable with cata-
lyst mediated reactions [10].
Based on the experimental observations and reported
mechanism for on-water mediated reactions [12], a
SCHEME 3 One-pot
approach for the Michael
adducts (10a-10e and 11a-11e)
and chromene-pyridine hybrids
(12a-12c) under catalyst-free
conditions
TABLE 3 Optimization of the
S. No.
Solvent (2 mL)
Oxidizing agent
SOCl2 (1.5 Eqv)
I2O5 (0.5 Eqv)
HCl (1 M)
Time (h)
Yield (%)a
70 [11a]
60 [11b]
55 [11c]
96 [11d]
conditions for the synthesis of
1
2
3
4
DMF
10
10
10
2
compound (13)
CH3CO2H + H2O
THF
tBuOH + H2O
I2 (1.1 Eqv)
Note: All of the reactions were performed with 1 mmol scale.
aIsolated yields.

6
NAGARAJU ET AL.
SCHEME 4 Synthesis of isoxazole-coumarin hybrids and 2-(3-cyano-2-oxo-2H-chromen-4-yl)acetic acid
3 | CONCLUSION
In conclusion, we have demonstrated an efficient and
green method for one-pot synthesis of functionalized
isoxazole-4H-chromene hybrids. Two independent
methods, o-hydroxy group directing cyclization of
isoxazole-styrenes
3,5-dimethyl-4-nitroisoxazole
and
Michael
on
addition
2-imino-2H-
of
SCHEME 5 Reduction of the nitro group of isoxazole into
amine (15)
chromene-3-carbonitrile are adopted using the “on-
water” concept. The developed methods were
extended for nitromethane, malononitrile, and
alkylcyanoacetates as Michael donors to give
chromene-pyridine hybrids. The resulting isoxazole-
4H-chromene hybrids were converted in to coumarins
13a-13e acetic acids.
plausible transition states are proposed as shown in
Supporting Information for both strategies (Figure S2). In
the method-A, salicylaldehyde reacts with an activated
3,5-dimethyl-4-nitroisoxazole to give Knoevenagel con-
densation product (I) and (II). The generated isoxazole
styrene further proceeds via 1,6-Michael addition with
malononitrile followed by Pinner type reaction (III) then,
the resulted compound fruther undergo proton migration
to give (IV). In the overall process, water is helping to
enhance the reaction kinetics in a synergistic way in the
presence of piperidine (Figure S1).
ACKNOWLEDGMENTS
S.N. thanks, UGC-New Delhi for the fellowship.
K.S. thanks DST for the INSPIRE fellowship.
D.K. thanks, DST (SERB), New Delhi for the financial
support (SB/FT/CS-136/2012 and SB/EMEQ-103/2014).
Whereas the method-B (catalyst-free reaction), an
intermediate (imine) is generated by Knoevenagel
condensation followed by cyclization to give
2-iminochromene. This reacts with the activated
3,5-dimethyl-4-nitroisoxazole in Michael fashion to
give the Michael adduct (III). The Michael adduct
further undergo proton migration to deliver the final
product (IV). In this case, poor solubility of the
starting materials in water helps aggregation. Also,
the hydrophobic effects of water (as reaction medium)
support the “on-water” concept for the success of the
reaction (Figure S2).
DATA AVAILABILITY STATEMENT
Supporting data is available
ORCID
Dhurke Kashinath https://orcid.org/0000-0002-2509-
0386
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How to cite this article: Nagaraju S, Sathish K,
Kashinath D. Synthesis of 4H-chromene-isoxazole
hybrids via ortho-hydroxy directing cyclization of
isoxazole-styrenes and Michael addition of imino-
chromenes in aqueous medium. J Heterocyclic
Chem. 2021;1–7. https://doi.org/10.1002/jhet.4251