Potassium iodate (KIO 3) as a novel reagent for the synthesis of isoxazolines: evaluation of antimicrobial activity of the products

Article abstract of DOI:10.1007/s12039-019-1622-9

Abstract : A novel reagent for the synthesis of isoxazolines has been reported. Aryl aldoximes were made to react with alkenes in the presence of KIO ₃ as the oxidising agent. This new reagent has been useful as an oxidant in the synthesis of i

Full text of DOI:10.1007/s12039-019-1622-9

J. Chem. Sci.
(2019) 131:46
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1622-9
REGULAR ARTICLE
Potassium iodate (KIO3) as a novel reagent for the synthesis of
isoxazolines: evaluation of antimicrobial activity of the products
SUMANA Y KOTIANa,∗ , P M ABISHAD b, K BYRAPPAb and K M LOKANATHA RAIa
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India
bDepartment of Studies in Earth Science, University of Mysore, Manasagangotri, Mysuru, Karnataka, India
E-mail: sumanakotian@gmail.com
MS received 3 October 2018; revised 15 March 2019; accepted 16 March 2019
Abstract. A novel reagent for the synthesis of isoxazolines has been reported. Aryl aldoximes were made
to react with alkenes in the presence of KIO3 as the oxidising agent. This new reagent has been useful as an
oxidant in the synthesis of isoxazoline and its function is attributed to the generation of nitrile oxide, which is
an important intermediate for the synthesis of the valuable heterocycle like isoxazoline.
Keywords. KIO3; oxidation; isoxazolines; antimicrobial.
1. Introduction
of DMAP in acetonitrile,10 (v) treatment of aldoximes
with magtrieve (CrO2) at 80 ◦C,11 (vi) β, γ -unsaturated
ketoximes reacted with 2-arylphenyl isonitriles in the
presence of t-BuOOH and n-Bu4NI,12 (vii) reaction of
aldoximes with alkenes in presence of CAT,13 (viii)
use of tert-butyl hypoiodite (t-BuOI) in dioxane in
the presence of 2,6- lutidine,14 (ix) reaction of aldehy-
des with hydroxylamine sulphate to obtain aldoximes
and then the formation of isoxazoline by the in situ
generated hypervalent iodine compound,15 (x) iodoben-
zene diacetate for the formation of nitrile oxides,16 (xi)
use of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-
mediated Cope-like elimination,17 and (xii) oxidation
of allyloximes by 2,2,2-trifluoroacetophenone in the
presence of H2O2.18 In view of the wide applica-
tions of isoxazoline, a literature survey revealed that
KIO3/KI in acetic acid can be used as an iodina-
tion agent at 110 ◦C.19 A polyol process was reported
for the synthesis of water dispersible anatase TiO2
nanoparticles by using KIO3.20 It is also reported as
a catalyst for the α-sulfenylation of enaminones.21
These reports prompted us to use KIO3, which turned
out as a novel oxidising agent for the synthesis of
isoxazolines. This metal-free process is less time con-
suming; in addition, the easy availability and stabil-
ity of KIO3 and effortless purification of the prod-
uct makes it a versatile reagent for the synthesis of
isoxazolines.
Among the various five-membered heterocycles,
2-isoxazolines have gained much attention as struc-
tural units of biologically potent compounds. They have
remarkable applications as intermediates in the synthe-
sis of numerous organic scaffolds. On the other hand,
these important synthetic intermediates can be easily
synthesized by 1,3-dipolar cycloaddition reaction of
alkenes with nitrile oxides generated in situ;1 this peri-
cyclic reaction is a versatile and effective tool for the
synthesis of isoxazolines from the chemically differ-
ent compounds. Isoxazolines have found applications
as antituberculosis agents,2 antibacterial agents, anti-
fungal agents,3 anticancer agents,4 anti-inflammatory
agents and COX-2 inhibitors. They are also found to
possess mesogenic core exhibiting liquid crystalline
properties.5,6 These varied applications have attracted
more interest in isoxazolines and their synthetic routes.
Various methods have been reported in the literature.
These include (i) condensation of ethyl benzoylac-
etate, aromatic aldehydes and hydroxylamine under
reflux condition in ethanol using DABCO,7 (ii) cycliza-
tion of N-alkenylamides catalyzed by iodoarenes under
oxidative conditions,8 (iii) Cu(OAc)2-catalyzed oxida-
tion of unsaturated alkenes,9 (iv) use of DMTMM
(4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpho-
linium chloride) as the dehydrating agent in the presence
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1622-9) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

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Scheme 1. Scheme of synthesis
Typically, cycloaddition reaction is carried out by compounds were poured into the well with 100 µg/mL con-
centration, and the sample volume being 75 µL. The plates
were kept for incubation at 37 ◦C for 24 h. After incubation,
the zone of inhibition was measured. DMSO (solvent) which
acts as a negative control was added in one well and in the
other well, gentamicin sulphate obtained from HIMEDIA was
added as a positive control.
heating an equimolar mixture of allyl bromide,
aldoxime, potassium iodate and acetic acid in ethanol
under reflux for 4–6 h. Among the synthesized com-
1
pounds, known compounds exhibited identical H and
13C NMR spectra, LC-MS, mixed MPs and TLC
behaviour with those of authentic samples. The plan of
synthesis is reported in Scheme 1.
2.2 Probable mechanistic pathway
The probable mechanistic pathway is given in Scheme 2. Gen-
eration of nitrile oxide involves the reaction of oxime with
iodic acid obtained from potassium iodate and acetic acid
to form oximino iodate. This undergoes disproportionation
to yield the nitrile oxide, which then underwent cycloaddi-
tion with alkenes to form the required isoxazolines in almost
quantitative yield.
2. Experimental
2.1 Materials and methods
The NMR analysis of the synthesized intermediates and final
compounds was carried out in AGILENT (400 MHz) NMR
spectrometer using deuterated chloroform as the solvent.
LC-MS of synthesized final products were obtained using
WATERS SynaptG2 model spectrometer. The completion of
the reaction was monitored by thin layer chromatography
2.3 Synthesis of isoxazolines
(TLC) performed on aluminium sheets coated with silica gel Alkylated benzaldehydes (1 mmol) and aldoximes (1 mmol)
obtained from Merck Kieselgel. All the chemicals were com- were prepared by reported methods.6 In a typical procedure,
mercially obtained and were used without further purification.
p-propoxy- benzaldoxime and allyl bromide were made to
Antibacterial activity of the synthesized compounds was react with KIO3 (1.2 mmol) for the generation of nitrile oxide
assessed by agar well diffusion method. The bacterial strains in situ under reflux conditions for 4–6 h in the presence of
used in this study were gram-negative bacteria such as Kleb- acetic acid in catalytic amount and ethanol as solvent. The
siella pneumonia (MTCC 661), Escherichia coli (MTCC completion of the reaction was monitored by TLC. After com-
1698), gram-positive bacteria such as Bacillus subtilus pletion, the residue was extracted with ether (25 mL × 3),
(MTCC 121), Staphylococcus aureus (MTCC 6908). 100 mL the extract was washed successively with water (15 mL × 2),
of Nutrient Agar was prepared and sterilized. 20 mL agar was 10% NaOH (15 mL × 2), and saturated brine solution
poured in each clean petri dish and was placed in a laminar (10 mL). TheorganiclayerwasdriedoveranhydrousNa2SO4.
airflow chamber. After solidification, 0.1 mL of the human The crude product was purified by recrystallization using
pathogenic bacteria was spread in the nutrient agar plate using methanol. The TLC and NMR spectra were compared with
the cotton swabs. Well of 10 mm diameter was formed in the standard compounds prepared using Chloramine-T and
the agar plates using well puncture apparatus. The prepared were found to be the same.

J. Chem. Sci.
(2019) 131:46
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46
Scheme 2. Probable mechanism
2.3a 5-(bromomethyl)-3-(4-propoxyphenyl)-4,5-
J = 6.4 Hz), 3.56–3.41 (m, 4H, CH2), 1.87–1.37 (m, 8H,
dihydroisoxazole (3a): Prepared from 2a and ii (allyl bro- CH2), 1.05 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
mide). White solid, Yield: 72%. 1H NMR (400 MHz, CDCl3): δ 160.87, 155.62, 128.29, 121.29, 121.21, 114.69, 114.52,
δ 7.59 (d, 2H, ArH, J = 8.4 Hz), 6.90 (d, 2H, ArH, J = 79.42, 68.15, 39.85, 33.22, 31.53, 29.10, 25.64, 22.56, 13.99.
8.4 Hz), 4.96 (m, 1H, OCH), 3.94 (t, 2H, OCH2, J = 6.4 Hz), Anal. Calcd for C16H22BrNO2: C – 56.48; H – 6.52; N – 4.12;
3.58–3.26 (m, 4H, CH2), 1.84–1.56 (m, 2H, CH2), 1.03 (t, Found: C - 56.13; H - 6.23; N - 3.91. LCMS [M+1]: Calcd
3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 160.88, 155.62, for C16H22BrNO2: 340.2, Found: 340.1.
128.29, 121.62, 121.30, 114.70, 114.59, 79.43, 69.63, 39.86,
33.16, 22.47, 10.42. Anal. CalcdforC13H16BrNO2:C-52.36;
H - 5.41; N - 4.70%; Found: C - 52.18; H - 5.01; N - 4.03%.
LCMS[M+1]:CalcdforC13H16BrNO2:298.1, Found:298.1.
2.3e 5-(bromomethyl)-3-(4-(heptyloxy)phenyl)-4,5-
dihydroisoxazole (3e): Prepared from 2e and ii (allyl bro-
mide). White solid; Yield: 70%; 1H NMR (400 MHz, CDCl3):
δ 7.56 (d, 2H, ArH, J = 8.4 Hz), 6.94 (d, 2H, ArH, J= 8.4
Hz), 4.72 (m, 1H, OCH), 3.96 (t, 2H, OCH2, J = 6.4 Hz),
2.3b 5-(bromomethyl)-3-(4-butoxyphenyl)-4,5-
dihydroisoxazole (3b): Prepared from 2b and ii (allyl 3.58–3.34 (m, 4H, CH2), 1.89–1.49 (m, 10H, CH2), 1.04 (t,
1
bromide). White solid; Yield: 71%; H NMR (400 MHz, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 160.87, 155.41,
CDCl3): δ 7.57 (d, 2H, ArH, J= 8.4 Hz), 6.97 (d, 2H, ArH, 128.34, 121.28, 121.19, 114.64, 114.43, 79.28, 69.57, 39.64,
J = 8.4 Hz), 4.88 (m, 1H, OCH), 3.97 (t, 2H, OCH2, 33.58, 29.34, 28.52, 27.26, 24.51, 22.37, 10.46. Anal. Calcd
J = 6.4 Hz), 3.51–3.36 (m, 4H, CH2), 1.86–1.44 (m, 4H, for C17H24BrNO2: C - 57.63; H - 6.83; N - 3.95; Found:
CH2), 1.01 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): C - 56.82; H - 6.01; N - 3.54. LCMS [M+1]: Calcd for
δ 161.79, 154.82, 128.34, 121.29, 121.18, 114.69, 114.62, C17H24BrNO2: 354.2, Found: 354.1.
79.34, 69.54, 39.26, 33.25, 29.69, 22.31, 10.51. Anal. Calcd
for C14H18BrNO2: C - 53.86; H - 5.81; N - 4.49; Found:
C - 53.32; H - 5.53; N - 4.14; LCMS [M+1]: Calcd for
C14H18BrNO2: 312.2, Found: 312.1.
2.3f 5-(bromomethyl)-3-(4-(octyloxy)phenyl)-4,5-
dihydroisoxazole (3f): Prepared from 2f and ii (allyl
1
bromide). White solid; Yield: 71%; H NMR (400 MHz,
CDCl3): δ 7.58 (d, 2H, ArH, J = 8.4 Hz), 6.90 (d, 2H,
2.3c 5-(bromomethyl)-3-(4-(pentyloxy)phenyl)-4,5-
ArH, J = 8.4 Hz), 4.95 (m, 1H, OCH), 3.97 (t, 2H, OCH2,
dihydroisoxazole (3c): Prepared from 2c and ii (allyl J = 6.4 Hz), 3.58–3.26 (m, 4H, CH2), 1.81–1.30 (m, 12H,
bromide).White solid; Yield: 69%; 1H NMR (400 MHz, CH2), 0.87 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
CDCl3): δ 7.57 (d, 2H, ArH, J = 8.4 Hz), 6.91 (d, 2H, δ 160.87, 155.63, 128.29, 128.19, 121.27, 114.69, 114.34,
ArH, J= 8.4 Hz), 4.78 (m, 1H, OCH), 3.99 (t, 2H, OCH2, 79.42, 68.15, 39.86, 33.21, 29.53, 29.31, 29.20, 29.13, 25.97,
J = 6.4 Hz), 3.54–3.38 (m, 4H, CH2), 1.88–1.47 (m, 6H, 22.63, 14.06. Anal. Calcd for C18H26BrNO2: C - 58.70; H –
CH2), 1.07 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): 7.12; N - 3.80; Found: C - 58.42; H - 6.91; N - 3.54. LCMS
δ 161.45, 155.25, 128.34, 121.25, 121.20, 114.59, 114.47, [M+2]: Calcd for C18H26BrNO2: 370.1, Found: 370.2.
79.43, 69.54, 39.71, 33.14, 29.48, 24.41, 22.39, 10.27. Anal.
Calcd for C15H20BrNO2: C – 55.83; H – 6.18; N – 4.29;
Found: C - 54.82; H - 5.83; N - 4.04. LCMS [M+1]: Calcd
for C15H20BrNO2: 326.2, Found: 326.1.
2.3g 5-(bromomethyl)-3-(4-(decyloxy)phenyl)-4,5-
dihydroisoxazole (3g): Prepared from 2g and ii (allyl
bromide). White solid; Yield: 70%;1H NMR (400 MHz,
CDCl3): δ 7.58 (d, 2H, ArH, J = 8.4 Hz), 6.90 (d, 2H,
ArH, J = 8.4 Hz), 4.94 (m, 1H, OCH), 3.96 (t, 2H, OCH2,
2.3d 5-(bromomethyl)-3-(4-(hexyloxy)phenyl)-4,5-
dihydroisoxazole (3d): Prepared from 2d and ii (allyl J = 6.4 Hz), 3.58–3.27 (m, 4H, CH2), 1.79–1.43 (m, 16H,
bromide).White solid; Yield: 73%; 1H NMR (400 MHz, CH2), 0.86 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ
CDCl3): δ 7.58 (d, 2H, ArH, J = 8.4 Hz), 6.94 (d, 2H, 160.87, 155.62, 128.29, 121.28, 114.68, 79.42, 77.37, 77.06,
ArH, J = 8.4 Hz), 4.81 (m, 1H, OCH), 3.91 (t, 2H, OCH2, 68.15, 39.85, 33.24, 31.87, 29.54, 29.35, 29.29, 29.20, 29.14,

46 Page 4 of 6
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25.98, 22.66, 14.09. Anal. CalcdforC20H30BrNO2:C-60.60; H - 9.12; N - 2.75; Found: C - 66.02; H - 9.02; N - 2.19. LCMS
H – 7.63; N - 3.53; Found: C - 60.01; H - 7.01; N - 3.41. LCMS [M+1]: Calcd for C28H46BrNO2: 508.5, Found: 508.1.
[M+2]: Calcd for C20H30BrNO2:398.3, Found: 398.2.
2.3l 5-(bromomethyl)-3-(4-methoxyphenyl)-4,5-
dihydroisoxazole (3l): Prepared from 2l and ii (allyl bro-
mide).White solid; Yield: 71%; 1H NMR (400 MHz, CDCl3):
δ 7.59 (d, 2H, ArH, J= 8.4 Hz), 6.90 (d, 2H, ArH, J =
8.4 Hz), 4.39 (m, 1H, OCH), 3.57 (s, 3H, OCH3), 3.56–3.25
(m, 4H, ArCH2). 13C NMR (CDCl3, 100 MHz): δ 160.74,
155.56, 128.19, 121.37, 121.24, 114.59, 114.46, 79.35, 69.38,
39.79, 33.17. Anal. Calcd for C11H12BrNO2: C - 48.91; H -
4.48; N - 5.19; Found: C - 48.18; H - 4.01; N - 5.03. LCMS
[M+1]: Calcd for C11H12BrNO2: 270.1, Found: 270.1.
2.3h 5-(bromomethyl)-3-(4-(dodecyloxy)phenyl)-4,
5-dihydroisoxazole (3h): Prepared from 2h and ii (allyl
bromide). White solid; Yield: 74%; 1H NMR(400 MHz,
CDCl3): δ 7.58 (d, 2H, ArH, J = 8.4 Hz), 6.90 (d, 2H, ArH,
J = 8.4 Hz), 4.95 (m, 1H, OCH), 3.97 (t, 2H, OCH2, J =
6.4 Hz), 3.57–3.26 (m, 4H, CH2), 1.81–1.25 (m, 20H, CH2),
0.86 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 160.89,
155.60, 128.28, 121.30, 114.71, 79.43, 77.29, 76.98, 76.66,
68.17, 39.86, 33.14, 31.87, 29.59, 29.54, 29.43, 29.32, 29.30,
29.13, 25.96, 22.64, 14.05. Anal. Calcd for C22H34BrNO2:
C - 62.26; H – 8.09; N - 3.30; Found: C - 62.06; H - 7.99; N -
3.24. LCMS [M+1]: Calcd for C22H34BrNO2: 424.4, Found:
424.1.
2.3m 5-(bromomethyl)-3-(3,4-dimethoxyphenyl)-4,5-
dihydroisoxazole (3m): Prepared from 2m and ii (allyl
1
bromide). White solid; Yield: 70%; H NMR (400 MHz,
CDCl3): δ 7.59 (d, 2H, ArH, J = 8.4 Hz), 6.91 (d, 1H, ArH,
J = 8.4 Hz), 4.39 (m, 1H, OCH), 3.58 (s, 6H, OCH3), 3.57–
3.26(m, 4H, ArCH2). 13CNMR(CDCl3, 100MHz):δ 160.86,
155.59, 128.34, 121.27, 121.59, 114.64, 114.48, 79.39, 69.57,
69.49, 39.59, 33.1. Anal. Calcd for C12H14BrNO3: C - 48.02;
H - 4.70; N - 4.67; Found: C - 47.81; H - 4.43; N - 4.43. LCMS
[M+1]: Calcd for C12H14BrNO3: 300.1, Found: 300.1.
2.3i 5-(bromomethyl)-3-(4-(tetradecyloxy)phenyl)-4,
5-dihydroisoxazole (3i): Prepared from 2i and ii (allyl
bromide). White solid; Yield: 70%; H NMR (400 MHz,
1
CDCl3): δ 7.58 (d, 2H, ArH, J= 8.4 Hz), 6.90 (d, 2H, ArH,
J = 8.4 Hz), 4.96 (m, 1H, OCH), 3.78 (t, 2H, OCH2,
J = 6.4 Hz), 3.57–3.26 (m, 4H, CH2), 1.81–1.25 (m, 24H,
CH2), 0.86 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
δ 160.89, 155.62, 129.29, 121.25, 121.18, 114.45, 114.37,
79.42, 68.26, 40.24, 39.85, 33.24, 31.87, 29.74, 29.54, 29.35,
29.29, 29.14, 28.16, 27.49, 27.14, 25.98, 22.66, 14.07. Anal.
Calcd for C24H38BrNO2: C - 63.71; H - 8.47; N – 3.10; Found:
C - 63.12; H - 8.19; N - 2.99. Calcd for C24H38BrNO2: 452.4,
Found: 452.1.
2.3n 5-(bromomethyl)-3-(4-bromophenyl)-4,5-
dihydroisoxazole (3n): Prepared from 2n and ii (allyl
bromide). White solid; Yield: 74%;1H NMR (400 MHz,
CDCl3): δ 7.57 (d, 2H, ArH, J = 8.4 Hz), 7.38 (d, 2H,
ArH, J = 8.4 Hz), 4.99 (m, 1H, OCH), 3.57–3.26 (m, 4H,
ArCH2). 13C NMR (CDCl3, 100 MHz): δ 160.82, 155.61,
128.24, 121.86, 121.72, 114.97, 114.78, 79.51, 39.98, 33.49.
Anal. Calcd for C10H9Br2NO: C - 37.65; H - 2.84; N - 4.39;
Found: C - 37.43; H - 2.73; N - 4.25. LCMS [M+1]: Calcd
for C10H9Br2NO: 318.9, Found: 318.3.
2.3j 5-(bromomethyl)-3-(4-(hexadecyloxy)phenyl)-4,
5-dihydroisoxazole (3j): Prepared from 2j and ii (allyl
1
bromide). White solid; Yield: 70%; H NMR (400 MHz,
CDCl3): δ 7.58 (d, 2H, ArH, J= 8.4 Hz), 6.90 (d, 2H, ArH,
J = 8.4 Hz), 4.95 (m, 1H, OCH), 3.97 (t, 2H, OCH2,
J = 6.4 Hz), 3.57–3.26 (m, 4H, CH2), 1.81–1.25 (m, 28H,
CH2), 0.87 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ
160.88, 155.62, 128.29, 121.27, 114.69, 79.43, 77.32, 77.01,
76.69, 68.16, 39.87, 33.19, 31.90, 29.66, 29.55, 29.35, 29.29,
29.20, 29.14, 28.69, 28.51, 28.19, 27.14, 25.98, 22.67, 14.09.
Anal. Calcd for C26H42BrNO2: C - 64.99; H – 8.81; N - 2.91;
Found: C - 64.08; H - 8.19; N - 2.28. LCMS [M+1]: Calcd
for C26H42BrNO2: 480.5, Found: 480.1.
2.3o 5-(bromomethyl)-3-(4-nitrophenyl)-4,5-
dihydroisoxazole (3o): Yield: 72%; Prepared from 2o
1
and ii (allyl bromide). Yellow solid; H NMR (400 MHz,
CDCl3): δ 7.56 (d, 2H, ArH, J = 8.4 Hz), 7.37 (d, 2H,
ArH, J = 8.4 Hz), 4.98 (m, 1H, OCH), 3.58–3.26 (m, 4H,
ArCH2). 13C NMR (CDCl3, 100 MHz): δ 160.81, 155.54,
128.31, 121.67, 121.32, 114.48, 114.43, 79.69, 39.43, 33.32.
Anal. Calcd for C10H9BrN2O3: C - 42.13; H - 3.18; N - 9.83;
Found: C - 42.04; H - 3.08; N - 9.47. LCMS [M+1]: Calcd
for C10H9BrN2O3: 286.1, Found: 286.1.
2.3k 5-(bromomethyl)-3-(4-(octadecyloxy)phenyl)-4,
5-dihydroisoxazole (3k): Prepared from 2k and ii (allyl 2.3p 5-(bromomethyl)-3-(4-fluorophenyl)-4,5-
1
bromide). White solid; Yield: 72%; H NMR (400 MHz, dihydroisoxazole (3p): Prepared from 2p and ii (allyl bro-
CDCl3): δ 7.58 (d, 2H, ArH, J= 8.4 Hz), 6.90 (d, 2H, ArH, mide).White solid; Yield: 70%;1H NMR (400 MHz, CDCl3):
J = 8.4 Hz), 4.96 (m, 1H, OCH), 3.97 (t, 2H, OCH2, δ 7.57 (d, 2H, ArH, J = 8.4 Hz), 7.38 (d, 2H, ArH, J =
J = 6.4 Hz), 3.57–3.26 (m, 4H, CH2), 1.81–1.25 (m, 32H, 8.4 Hz), 4.99 (m, 1H, OCH), 3.57–3.26 (m, 4H, ArCH2). 13
C
CH2), 0.88 (t, 3H, CH3). 13C NMR (CDCl3, 100 MHz): NMR (CDCl3, 100 MHz): δ 160.82, 155.61, 128.24, 121.86,
δ 160.79, 155.67, 128.18, 129.04, 121.24, 114.29, 114.21, 121.72, 114.97, 114.78, 79.51, 39.98, 33.49. Anal. Calcd for
79.57, 68.02, 40.08, 39.79, 33.08, 31.87, 29.57, 29.51, 29.47, C10H9BrFNO: C - 46.54; H - 3.51; N - 5.43; Found: C - 46.31;
29.40, 29.38, 29.31, 29.27, 29.24, 28.57, 28.48, 28.38, 27.34, H - 3.23; N - 5.16. LCMS [M+1]: Calcd for C10H9BrFNO:
25.87, 22.75, 14.12. Anal. CalcdforC28H46BrNO2:C-66.13; 257.1, Found: 257.1.

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46
Table 1. Determination of the MIC by Resazurin aided
microdilutionmethodofsynthesizedcompoundsagainststan-
dard pathogens.
MIC reported in this
study (mg mL−1
)
Bacteria
Compounds
Klebsiella pneumoniae
Escherichia coli
4r
4r
4j
0.75
0.75
1.25
1.25
1.25
1.25
1.25
2.5
Klebsiella pneumoniae
Staphylococcus aureus
Klebsiella pneumoniae
Staphylococcus aureus
Staphylococcus aureus
Bacillus cereus
4j
4q
4p
4n
4n
Figure 1. Graphical representation of the zone of inhibition
exhibited by the synthesized compounds.
2.3q 5-(bromomethyl)-3-(4-chlorophenyl)-4,5-
dihydroisoxazole (3q): Prepared from 2q and ii (allyl
bromide). White solid; Yield: 72%;1H NMR (400 MHz,
CDCl3): δ 7.58 (d, 2H, ArH, J = 8.4 Hz), 7.36 (d, 2H,
ArH, J = 8.4 Hz), 4.99 (m, 1H, OCH), 3.57–3.24 (m, 4H,
ArCH2). 13C NMR (CDCl3, 100 MHz): δ 160.84, 155.57,
128.31, 121.28, 121.58, 114.65, 114.49, 79.38, 39.54, 33.17.
Anal. Calcd for C10H9BrClNO: C - 43.75; H - 3.30; N - 5.10;
Found: C - 43.17; H - 3.21; N - 5.03. LCMS [M+1]: Calcd
for C10H9BrClNO: 275.5, Found: 275.4.
is not known well, it is believed that the synthesized com-
pounds get adhered on the cell wall of the bacteria, which
results in the lysis of the cell thus proving it to be fatal.22
From the results obtained, it can be inferred that com-
pound 4r exhibited excellent inhibitory activity against both
gram-negative bacterial strains; this might be attributed to the
presence of the F atom in the third position. The presence
of halogens usually will increase the inhibitory effect. Com-
pound 4n was found to exhibit inhibitory activity against both
gram-positive bacterial strains, probably due to the presence
of Br atom. Compound 4q exhibited good inhibitory activity
against Klebsiella pneumoniae and 4p exhibited appreciable
inhibitory activity against Staphylococcus aureus. It is evi-
dent from the results that halogen substituents do contribute
tothe inhibitionactivitymaybedue tothe presenceof electron
withdrawing nature (Table 1).
2.3r 5-(bromomethyl)-3-(3-fluorophenyl)-4,5-
dihydroisoxazole (3r): Prepared from 2r and ii (allyl bro-
mide). White solid; Yield: 74%;1H NMR (400 MHz, CDCl3):
δ 7.58 (d, 2H, ArH, J= 8.4 Hz), 7.36 (d, 2H, ArH, J =
8.4 Hz), 4.99 (m, 1H, OCH), 3.57–3.24 (m, 4H, ArCH2). 13
C
NMR (CDCl3, 100 MHz): δ 160.84, 155.62, 128.34, 121.29,
121.57, 114.46, 114.38, 79.29, 39.57, 33.09. Anal. Calcd for
C10H9BrFNO: C - 46.54; H - 3.51; N - 5.43; Found: C - 46.14;
H - 3.47; N - 5.21. LCMS [M+1]: Calcd for C10H9BrFNO:
258.1, Found: 258.1.
3. Conclusions
A novel metal-free benign procedure is reported for
the synthesis of isoxazolines. Aryl aldehydes were con-
verted to aldoximes in the presence of hydroxylamine
hydrochloride and sodium acetate. Later, they were
made to react with alkenes in the presence of the novel
2.3s 5-(bromomethyl)-3-(1,3-dihydroisobenzofuran-
5-yl)-4,5-dihydroisoxazole (3s): Prepared from 2s and
ii (allyl bromide). White solid; Yield: 72%; H NMR (400
1
MHz, CDCl3): δ 7.48 (d, 1H, ArH, J = 8.4 Hz), 7.36 (s, 1H,
ArH), 6.86 (d, 1H, ArH, J = 8.4 Hz), 6.02 (s, 4H), 4.99 (m, reagent – KIO3 which acts as an oxidising agent. The
1H, OCH), 3.58–3.26 (m, 4H, ArCH2). 13C NMR (CDCl3,
obtained products are important heterocycles as they can
100 MHz): δ 160.79, 155.58, 128.34, 121.87, 121.59, 114.56,
114.54, 79.35, 39.79, 33.24. Anal. Calcd for C12H12BrNO2:
C - 51.09; H - 4.29; N - 4.96; Found: C - 51.01; H - 4.21; N -
4.53. LCMS [M+1]: Calcd for C12H12BrNO2: 282.1, Found:
282.1.
be further used for Suzuki coupling or Heck reactions
to obtain pharmaceutically potent drugs. Other applica-
tions are under investigation.
Supporting Information (SI)
Detailed Results and Discussion with 1H and 13C NMR, LC-
MS and biological assay images are available at www.ias.ac.
in/chemsci.
2.4 Biological assay
The plates were analysed for the zone of inhibition and the
results obtained are represented graphically in Figure 1. The
appearance of the inhibition zone around the well indicates
Acknowledgements
antimicrobial activity of the synthesized isoxazoline deriva- One of the authors, SYK, acknowledges the University of
tives. However, the mode of action caused by the compounds Mysore for the laboratory facilities. SYK also acknowledges

46 Page 6 of 6
J. Chem. Sci.
(2019) 131:46
the Institute of Excellence, the University of Mysore for the 11. BhosaleS, KurhadeS, PrasadUV, PalleVP and Bhuniya
D2009Efficient synthesis ofisoxazoles andisoxazolines
from aldoximes using MagtrieveTM(CrO2) Tetrahedron
Lett. 50 3948
instrumentation facilities. Author APM is grateful to Univer-
sity with Potential for excellence, the University of Mysore
for the financial assistance provided to carry out this work.
12. Yang X L, Chen F, Zhou N N, Yu W and Han B 2014 Syn-
thesisofIsoxazoline-FunctionalizedPhenanthridinesvia
Iminoxyl Radical-Participated Cascade Sequence Org.
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sisofnewseries3, 4, 5-trisubstituted-dihydroisoxazoline
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Compliance with ethical standards
Conflict of interest Authors declare no conflict of interest.
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