Facile and expedient synthesis of α,β-unsaturated isoxazol-5(4H)-ones under mild conditions

Article abstract of DOI:10.1007/s11164-019-03999-7

Abstract: It was found that nano-SiO₂–H₂SO₄ was catalyzed by the three-component cyclocondensation of aryl/heteroaryl aldehydes, hydroxylamine hydrochloride, and β-ketoesters toward the synthesis of α,β-unsaturated?isoxazol-5(4H)-ones under green conditions. The reaction yielded the corresponding heterocycles at room temperature in relatively shorter reaction times. It merits mentioning that the mild conditions allow the synthesis of several α,β-unsaturated?isoxazol-5(4H)-ones using this method. In this study, some new derivatives of isoxazolones were also synthesized and characterized. It is efficient, clean, simple, safe, and ecologically friendly. This straightforward method is cost-effective and requires no preparation of reactants. The three-component annulation was performed without using energy sources, for example, heat, ultrasound wave, and microwave irradiation. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-019-03999-7

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03999-7
Facile and expedient synthesis of α,β‑unsaturated
isoxazol‑5(4H)‑ones under mild conditions
Fatemeh Ghorbani1 · Hamzeh Kiyani1 · Seied Ali Pourmousavi1
Received: 22 July 2019 / Accepted: 1 October 2019
© Springer Nature B.V. 2019
Abstract
It was found that nano-SiO2–H2SO4 was catalyzed by the three-component cyclo-
condensation of aryl/heteroaryl aldehydes, hydroxylamine hydrochloride, and
β-ketoesters toward the synthesis of α,β-unsaturated isoxazol-5(4H)-ones under
green conditions. The reaction yielded the corresponding heterocycles at room tem-
perature in relatively shorter reaction times. It merits mentioning that the mild con-
ditions allow the synthesis of several α,β-unsaturated isoxazol-5(4H)-ones using this
method. In this study, some new derivatives of isoxazolones were also synthesized
and characterized. It is efcient, clean, simple, safe, and ecologically friendly. This
straightforward method is cost-efective and requires no preparation of reactants.
The three-component annulation was performed without using energy sources, for
example, heat, ultrasound wave, and microwave irradiation.
Graphic abstract
Extended author information available on the last page of the article
Vol.:(0123456789)
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F. Ghorbani et al.
Keywords Green synthesis · Hydroxylamine hydrochloride · Isoxazol-5(4H)-ones ·
β-Ketoester · Nano-SiO2–H2SO4 · Three-component reaction
Introduction
Multicomponent reactions (MCRs) are efective methods to the practical construc-
tion of a wide range of heterocyclic compounds in single operation with structural
diversity and complexity from simple and inexpensive starting materials via the
generation of several bonds in a single synthetic operation. Recently, signifcant
consideration has been attentive to MCRs due to their simplicity, the diminished
generation of the waste, shorter reaction times, step/atom economy, reduced steps
of purifcation of intermediates, mild reaction conditions, as well as environmental
benignity [1–7].
The isoxazol-5(4H)-one, also called isoxazolone, ring systems represent impor-
tant molecular structures, which have been employed as the precursors in the syn-
thesis of interesting organic molecules [8, 9]. They have been known to show anti-
bacterial [10], antifungal [10–12], tyrosinase inhibitory [13], anticancer [14–16],
anti-obesity [17, 18], anti-androgen [19, 20], CDP-ME kinase inhibitor [21], anti-
HIV-1 [22], fungicide [23], and insecticides [24, 25] activities. Also, the isoxazol-
5(4H)-one motifs as the powerful electron acceptor are likely to be good candi-
dates for organic nonlinear optical (NLO) materials [26–28], photonic applications
[29–32], and solar cells [33]. Some of the α,β-unsaturated isoxazol-5(4H)-one deriv-
atives that show strong biological activities are presented in Fig. 1.
As mentioned above, α,β-unsaturated isoxazol-5(4H)-ones play an important role
in the organic synthetic chemistry. Therefore, organic chemists are interested in the
synthesis of such heterocycles in recent years. One of the most attractive methods
of obtaining isoxazol-5(4H)-ones is the cyclocondensation of hydroxylamine hydro-
chloride with β-ketoesters and various aldehydes in the presence of various types of
catalysts, including sodium acetate and tungsten lamp [34], potassium phthalimide
(PPI) [35], potassium hydrogen phthalate (KHP) [36], tetrabutylammonium perchlo-
rate (TBAP)/glycine/sodium oxalate [37], 2-hydroxy-5-sulfobenzoic acid (2-HSBA)
[38], N-bromosuccinimide (NBS) [39], Ag/SiO2 [40], fruit juice of citrus Limon
[41], amine-modifed montmorillonite nanoclay [42], sodium benzoate [12, 43],
boric acid [44], SnII montmorillonite [45], nickel (II) acetate [46], citric acid [47],
starch solution [48], sulfated polyborate [49], pyridinium p-toluenesulfonate (PPTS)
[50], DABCO-functionalized dicationic ionic liquid (DDIL) [51], Na2S·9H2O
[52], nano-MgO [53], pyridine [54–56], sulfanilic acid [57], KI [58], sodium sili-
cate [59], deep eutectic solvent [60], mesolite [61], cerium chloride heptahydrate
[62], phthalimide-N-oxyl [63], antimony trichloride [64], DOWEX1-x8OH [65],
LiBr [66], and salicylic acid [67]. In the recent years, sulfuric acid supported on
silica (SiO2–H2SO4) as an efcient and environmental-friendly solid acid catalyst
has been applied in organic transformations due to their high catalytic activity, the
operational simplicity, cost-efectiveness, and the recyclability. Using this conveni-
ent, safe, and highly efcient catalyst will make the products formed in high yields
as well as facilitating the product separation and purifcation processes [68–73]. In
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Facile and expedient synthesis of α,β-unsaturated…
Fig. 1 Selected examples of α,β-unsaturated isoxazol-5(4H)-ones with biological activities
the present study, an expeditious, one-pot, three-component cyclocondensation has
been used for the green synthesis of derivatives of α,β-unsaturated isoxazol-5(4H)-
ones (4a–4aq) applying nano-SiO2–H2SO4 as the catalyst under mild conditions
(Scheme 1). In this contribution, the synthesis of ffteen derivatives of isoxazol-
5(4H)-one is also presented for the frst time.
Experimental
General
All chemicals were purchased from Alfa Aesar and Aldrich and were used with-
out further purifcation, with the exception of liquid aldehydes which were distilled
and purifed before using. All solvents were distilled before using. Melting points
were measured on a Buchi 510 melting point apparatus and are uncorrected. Nuclear
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F. Ghorbani et al.
Scheme 1 Three-component synthesis of α,β-unsaturated isoxazol-5(4H)-ones (4a–4aq)
magnetic resonance (NMR) spectra were recorded at an ambient temperature on a
Bruker Avance DRX-300 MHz using DMSO-d6 as the solvent. FT-IR spectra were
recorded on a PerkinElmer RXI spectrometer. The development of reactions was
monitored by thin-layer chromatography (TLC) analysis on Merck pre-coated silica
gel 60 F254 aluminum sheets, visualized by UV light. Elemental microanalyses were
performed on an Elementar Vario EL III analyzer. SEM images were taken using
a JEOL JSM-5300 microscope at acceleration voltage of 10 kV. Sample powder
was deposited on a carbon tape before mounting on a sample holder. To reduce the
charge developed on the sample, gold sputtering was done for 3 min.
General procedure for the synthesis of α,β‑unsaturated isoxazol‑5(4H)‑ones
(4a–4aq)
A mixture of hydroxylamine hydrochloride 2 (0.0695 g, 1 mmol), β-ketoester
3 (1 mmol), and catalyst (0.05 g) in 5 mL of distilled water was stirred at room
temperature (rt) for 10 min; then, aryl/heteroaryl aldehyde 1 (1 mmol) was added
to the vessel reaction. The reaction mixture was stirred at rt until the reaction was
completed (monitored by TLC analysis). After the completion of the reaction, the
precipitate was separated by simple fltration, washed with cold distilled water, and
dried in the air. Crude products were dissolved in hot ethanol and fltered of for the
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Facile and expedient synthesis of α,β-unsaturated…
separation of catalyst. The products were crystallized from ethanol (95%) to aford
the title pure compounds. Spectral data for some compounds are as follows:
4‑(2‑Hydroxy‑3‑methoxybenzylidene)‑3‑methylisoxazol‑5(4H)‑one (4i)
1H NMR (300 MHz, DMSO-d6): δ=2.25 (s, 3H, CH3), 3.85 (s, 3H, CH3O), 6.88 (t,
J=8.1 Hz, 1H, Ar–H), 7.25 (dd, J=1.2, 8.1, 1H, Ar–H), 8.10 (s, 1H, ArCH═), 8.31
(dd, J=1.2, 8.4 Hz, 1H, Ar–H), 10.35 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6):
δ=27.4, 75.4, 116.7, 118.7, 119.7, 139.4, 144.9, 147.7, 149.4, 152.8, 162.1, 176.0;
IR (KBr, cm−1): ν=3418, 1750, 1620, 1357, 1257, 1095, 935.
3‑Methyl‑4‑(3,4,5‑trimethoxybenzylidene)isoxazol‑5(4H)‑one (4k)
1H NMR (CDCl3, 400 MHz): δ=2.32 (s, 3H, CH3), 3.98 (s, 6H, meta-CH3O), 4.02
(s, 3H, para-CH3O), 7.34 (s, 1H, ArCH═), 7.86 (s, 2H, Ar–H); 13C NMR (DMSO-
d6, 100 MHz): δ=11.6, 56.4, 61.2, 111.8, 117.9, 122.7, 127.7, 149.8, 152.9, 161.1,
168.5.
4‑(4‑(Bis(2‑chloroethyl)amino)benzylidene)‑3‑methylisoxazol‑5(4H)‑one (4l)
1H NMR (300 MHz, DMSO-d6): δ=2.21 (s, 3H, CH3), 3.81 (t, J=6.0 Hz, 4H,
2×CH2), 3.91 (t, J=6.9 Hz, 4H, 2×CH2Cl), 6.97 (d, J=9.3 Hz, 2H, Ar–H), 7.65
(s, 1H, ArCH═), 8.45 (d, J=8.7 Hz, 2H, Ar–H); 13C NMR (75 MHz, DMSO-d6):
δ=11.3, 40.9, 51.6, 110.9, 112.0, 122.1, 137.4, 150.5, 152.1, 162.1, 169.4.
(4‑(4‑Hydroxy‑3,5‑dimethoxybenzylidene)‑3‑methylisoxazol‑5(4H)‑one (4n)
1H NMR (300 MHz, DMSO-d6): δ=2.23 (s, 3H, CH3), 3.83 (s, 6H, 2×CH3O), 7.74
(s, 1H, ArCH═), 8.03 (s, 2H, Ar–H), 10.2 (s, 1H, OH); 13C NMR (75 MHz, DMSO-
d6): δ=11.3, 56.0, 112.7, 113.9, 123.7, 143.2, 147.5, 152.1, 162.2, 169.0.
4‑((2‑Hydroxynaphthalen‑1‑yl)methylene)‑3‑methylisoxazol‑5(4H)‑one (4q)
1H NMR (300 MHz, DMSO-d6): δ=2.41 (s, 3H, CH3), 7.58–7.68 (m, 3H, Ar–H and
ArCH═), 8.02 (d, J=8.4 Hz, 1H, Ar–H), 8.15 (d, J=8.4 Hz, 1H, Ar–H), 8.29 (d,
J=8.1 Hz, 1H, Ar–H), 8.45 (d, J=7.5 Hz, 1H, Ar–H), 8.63 (s, 1H, OH); 13C NMR
(75 MHz, DMSO-d6): δ=11.3, 120.3, 124.4, 124.9, 126.6, 127.5, 128.9, 130.8,
131.4, 132.9, 148.5, 158.9, 161.9, 167.5, 169.2.
3‑Methyl‑4‑((5‑methylthiophen‑2‑yl)methylene)isoxazol‑5(4H)‑one (4s)
1H NMR (300 MHz, DMSO-d6): δ=2.24 (s, 3H, CH3 of thiophen ring), 2.61 (s,
1H, CH3 of isoxazolone ring), 7.13 (dd, J=0.77, 3.80 Hz, 1H, Ar–H), 8.04 (d,
J=3.8 Hz, 1H, Ar–H), 8.11 (s, 1H, ArCH═); 13C NMR (75 MHz, DMSO-d6):
δ=11.0, 15.9, 111.2, 128.3, 134.4, 141.6, 144.3, 157.1, 161.5, 168.7; IR (KBr,
cm−1): ν=3432, 1735, 1599, 1431, 1147, 1110, 1064, 998.
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F. Ghorbani et al.
3‑Methyl‑4‑((E)‑3‑phenylallylidene)isoxazol‑5(4H)‑one (4t)
1H NMR (300 MHz, DMSO-d6): δ=2.30 (s, 1H, CH3 of isoxazolone ring),
7.46–7.66 (m, 6H, Ar–H and CH=), 7.75 (d, J=11.7 Hz, 1H,=CH), 8.06–8.15
(m, 1H, CH═); 13C NMR (75 MHz, DMSO-d6): δ=10.8, 116.9121.8, 128.7, 129.3,
134.8, 136.8, 149.6, 151.8, 168.7, 173.4.
3‑(Chloromethyl)‑4‑(2‑hydroxy‑3‑methoxybenzylidene)isoxazol‑5(4H)‑one (4aa)
1H NMR (300 MHz, DMSO-d6): δ=3.85 (s, 3H, CH3O), 4.89 (s, 2H, CH2Cl), 6.89
(t, J=8.1 Hz, 1H, Ar–H), 7.27 (d, J=8.0 Hz, 1H, Ar–H), 8.35 (d, J=8.2 Hz, 1H,
Ar–H), 8.40 (s, 1H, ArCH═), 10.45 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6):
δ=35.3, 56.1, 113.1, 118.2, 118.7, 119.6, 123.4, 146.7, 147.7, 150.0, 161.5, 167.6;
IR (KBr, cm−1): ν=3416, 1752, 1622, 1376, 1260, 1090, 934.
3‑(Chloromethyl)‑4‑(3,4‑dimethoxybenzylidene)isoxazol‑5(4H)‑one (4ab)
1H NMR (300 MHz, DMSO-d6): δ=3.84 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 4.87
(s, 2H, CH2Cl), 7.23 (d, J=8.6 HZ, 1H, Ar–H), 8.01 (d, J=6.7 HZ, 1H, Ar–H),
8.05 (s, 1H, Ar–H), 8.48 (s, 1H, ArCH═); 13C NMR (75 MHz, DMSO-d6): δ=35.0,
111.4, 111.8, 125.8, 131.7, 148.4, 152.8, 155.1, 161.6, 168.3; IR (KBr, cm−1):
ν=3442, 3099, 2950, 1743, 1554, 1523, 1279, 1140, 1033, 885.
3‑(Chloromethyl)‑4‑(3,4,5‑trimethoxybenzylidene)isoxazol‑5(4H)‑one (4ac)
1H NMR (300 MHz, DMSO-d6): δ=3.84 (s, 3H, CH3O), 3.86 (s, 6H, CH3O), 4.87
(s, 2H, CH2Cl), 7.97 (s, 2H, Ar–H), 8.09 (s, 1H, ArCH═); 13C NMR (75 MHz,
DMSO-d6): δ=34.9, 56.0, 112.2, 113.6, 127.6, 143.6, 152.4, 152.9, 161.6, 167.8; IR
(KBr, cm−1): ν=3434, 2941, 1725, 1570, 1426, 1349, 1258, 1125, 1112, 990.
4‑(4‑(Bis(2‑chloroethyl)amino)benzylidene)‑3‑(chloromethyl)isoxazol‑5(4H)‑one
(4ad)
1H NMR (300 MHz, DMSO-d6): δ=3.82 (t, J=6.7 Hz, 4H, 2×CH2), 3.94 (t,
J=6.2 Hz, 4H, 2×CH2Cl), 4.83 (s, 2H, CH2Cl), 7.04 (d, J=9.2 Hz, 2H, Ar–H),
7.87 (s, 1H, ArCH═), 8.47 (d, J=8.9 Hz, 2H, Ar–H); 13C NMR (75 MHz, DMSO-
d6): δ=35.2, 40.9, 51.6, 106.8, 112.4, 121.9, 137.9, 151.4, 152.9, 161.6, 169.1; IR
(KBr, cm−1): ν=3432, 1740, 1565, 1545, 1353, 1185, 1043, 933.
4‑(4‑(Bis(2‑chloroethyl)amino)benzylidene)‑3‑phenylisoxazol‑5(4H)‑one (4al)
1H NMR (300 MHz, DMSO-d6): δ=3.83 (t, J=6.0 Hz, 4H, 2×CH2), 3.95 (t,
J=6.8 Hz, 4H, 2×CH2), 6.99 (d, J=9.1 Hz, 1H, Ar–H), 7.56 (s, 1H, ArCH═),
7.56–7.64 (m, 5H, Ar–H), 8.45 (d, J=9.0 Hz, 2H, Ar–H); 13C NMR (75 MHz,
1 3

Facile and expedient synthesis of α,β-unsaturated…
DMSO-d6): δ=40.9, 51.5, 109.3, 112.1, 121.9, 127.9, 128.7, 129.1, 130.5, 137.9,
152.6, 164.4, 169.6; IR (KBr, cm−1): ν=3435, 1742, 1550, 1526, 1351, 1184, 1092,
828.
4‑(4‑hydroxybenzylidene)‑3‑propylisoxazol‑5(4H)‑one (4am)
1H NMR (500 MHz, DMSO-d6): δ=0.99 (t, J=7.3 Hz, 3H, CH2CH3), 1.68 (sext,
J=7.4 Hz, 2H, CH2CH3), 2.66 (t, J=7.4, 2H, CH2), 6.95 (d, J=8.3 Hz, 2H, Ar–H),
7.84 (s, 1H, ArCH═), 8.47 (d, J=8.3 Hz, 2H, Ar–H); 13C NMR (125 MHz, DMSO-
d6): δ=14.1, 19.9, 27.5, 113.6, 116.6, 125.1, 138.0, 151.5, 164.3, 165.2, 169.5.
4‑(4‑(Dimethylamino)benzylidene)‑3‑propylisoxazol‑5(4H)‑one (4an)
1H NMR (300 MHz, DMSO-d6): δ=0.95 (t, J=7.4 Hz, 3H, CH3), 1.65 (sext,
J=7.4 Hz, 2H, CH2CH3), 2.55 (t, J=7.6 HZ, 2H, CH2), 3.10 (s, 6H, N(CH3)2), 6.81
(d, J=9.2, 2H, Ar–H), 7.58 (s, 1H, ArCH═), 8.44 (d, J=9.0 2H, ArH); 13C NMR
(75 MHz, DMSO-d6): δ=13.7, 19.6, 27.1, 39.6, 108.3, 111.5, 120.9, 137.5, 149.9,
154.2, 164.6, 169.9; IR (KBr, cm−1): ν=2925, 1710, 1552, 1528, 1341, 1199, 1113,
1033.
4‑(3,4‑Dimethoxybenzylidene)‑3‑propylisoxazol‑5(4H)‑one (4ao)
1H NMR (300 MHz, DMSO-d6): δ=0.97 (t, J=7.4 Hz, 3H, CH3), 1.65 (sext,
J=7.4, 2H, CH2CH3), 2.60 (t, J=7.4 Hz, 2H, CH2), 3.81 (s, 3H, CH3O), 3.88 (s,
3H, CH3O), 7.13 (d, J=8.6 Hz, 1H, Ar–H), 7.79 (s, 1H, ArCH═), 7.98 (dd, J=1.6,
8.3, Hz, 1H, Ar–H), 8.45 (d, J=1.6 Hz, 1H, Ar–H); 13C NMR (75 MHz, DMSO-
d6): δ=13.6, 19.2, 27.0, 55.4, 55.9, 111.4, 114.3, 115.6, 126.0, 131.0, 148.3, 151.1,
154.3, 164.6, 168.9.
3‑Propyl‑4‑(3,4,5‑trimethoxybenzylidene)isoxazol‑5(4H)‑one (4ap)
1H NMR (300 MHz, DMSO-d6): δ=0.98 (t, J=3.3 Hz, 3H, CH3), 1.68 (sext,
J=7.5 Hz, 2H, CH2CH3), 2.63 (t, J=7.7 Hz, 2H, CH2), 3.81 (s, 3H, CH3O), 3.83
(s, 6H, 2×CH3O), 7.87 (s, 1H, ArCH═), 7.99 (s, 2H. Ar–H); 13C NMR (75 MHz,
DMSO-d6): δ=13.6, 19.2, 27.1, 55.9, 60.4, 112.0, 116.4, 127.9, 142.9, 151.2, 152.3,
164.6, 168.5; IR (KBr, cm−1): ν=2946, 1742, 1410, 1570, 1492, 1340, 1132, 997.
4‑(4‑(Bis(2‑chloroethyl)amino)benzylidene)‑3‑propylisoxazol‑5(4H)‑one (4aq)
1H NMR (300 MHz, DMSO-d6): δ=0.97 (t, J=7.4 Hz, 3H, CH3), 1.66 (sext,
J=7.4 Hz, 2H, CH2CH3), 3.82 (t, J=6.6 Hz, 2H, 2×CH2N), 3.92 (t, J=6.1 Hz,
2H, 2×CH2Cl), 6.98 (d, J=9.2 Hz, 2H, Ar–H), 7.69 (s, 1H, ArCH═), 8.49 (d,
J=9.0 Hz, 2H, Ar–H); 13C NMR (75 MHz, DMSO-d6): δ=13.7, 19.5, 27.0, 41.0,
51.6, 110.3, 111.5, 112.0, 122.1, 137.5, 150.1, 152.1, 164.7, 169.6. IR (KBr, cm−1):
ν=2967, 1725, 1629, 1597, 1525, 1324, 1259, 1134, 892.
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F. Ghorbani et al.
Results and discussion
At a frst step, nanosilica was synthesized according to the previously reported
method [74]. Sulfuric acid immobilized on nano-SiO2 was also synthesized
according to the literature [69]. To synthesize the nano-SiO2–H2SO4, a concen-
trated sulfuric acid was gradually added to a mortar containing nano-SiO2. The
mixture was stirred for 15 min and then placed in the oven at 100 °C for 12 h. In
this process, the FE-SEM images revealed that the SiO2–H2SO4 particles were
formed at the nanoscale (Fig. 2). The particle size of the SiO2–H2SO4 particles
typically ranges between 25 and 55 nm.
Fig. 2 FE-SEM of synthesized nano-SiO2–H2SO4
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Facile and expedient synthesis of α,β-unsaturated…
After the synthesis of nanocatalyst, the three-component cyclocondensation
(3-CC) of vanillin (1h), hydroxylamine hydrochloride (2), and ethyl acetoacetate
(3a) was selected as the model reaction to establish the optimum reaction con-
ditions (Fig. 3). Implementation of the reaction under catalyst-free conditions
did not obtain pleasing results. Therefore, a catalyst was used. Satisfyingly, an
expected heterocyclic product (4h) was obtained under the catalysis of nano-
SiO2–H2SO4 (0.025 g) in 45% isolated yield after 30 min using water as the sol-
vent at rt. Concomitant increase in the reaction time from 45 min to 2 h increased
the reaction yield to 60%, but due to the long reaction time this change is not a
desirable result. Water is close to being an ideal green solvent, preferable to alter-
natives such as organic solvents [1]. For this reason, water was used to carry out
these 3-CCs. It should be noted that a prolonged reaction time had no signifcant
efect on the reaction yield. Screening of the catalyst loading at rt revealed 0.05 g
to be the best choice, delivering 4h in 90% isolated yields. The yield of 4h was
not improved when the catalyst amount was increased from 0.05 to 0.75, 0.10,
and 0.125 g at rt. The screening reaction temperatures (50, 75 °C and refux)
showed that increasing temperature did not have positive efect on the reaction
yield (see red font in Fig. 3). The efects of the solvent was then investigated and
found that ethanol, acetone, ethyl acetate, n-hexane, and a mixture of water–etha-
nol did not give better results (see blue font in Fig. 3). When the reaction was
performed under solvent-free conditions, the target product was obtained in 15%
isolated yield. In summary, when vanillin (1h) was treated with 2 and 3a using
cat.
cat.
=
room
rt
Optimized
conditions
temperature
cat.
H
0.025
rt
H2
0.05
2O,
mi rt
n
30
O,
45%
g
g
,
,
30
mi
cat.
90
n
H
90%
%
0.05
solvent-free,
2 O,
0.75
15%,
g
rt
,
g
120
30
HO
OCH3
rt
cat.
H
cat. 0.05
g
0.05
g
mi
mi
n
n
50 °C
2O,
H
reflux
2O,
O
min
30
88%,
30 min
68%,
NH
cat.
2OH.HCl
H
91%,
g
0.10
1h
no
cat.
rt
CHO
+
2O,
0.05
rt
OEt
3a
2
n
rt
30
H
g
2O,
60%,
cat.
mi
O
120 min
120
acetone,
H
3CO
mi
n
10%,
g
rt
,
mi
0.05
CH3
cat. 0.05
g
HO
cat.
n
75 °C
H
72%,
2O,
n
g
-hexane
cat.
120
,
n
min
30
N
0.125
O
mi
4h
5%
H2
rt
0.05
O
0
O,
,
g
rt
30
84%,
12
cat.
EtOAc,
15%,
cat.
EtOH
50%,
cat.
0.05
mi
0.05
n
EtOH-H
g
g
rt
rt
,
2O
80%
120
(1:1),
mi
,
120
mi
The blue font is used
to show the solvent
effect.
The red font is used
n
n
to show the
effect.
temperature
Fig. 3 Screening of the reaction conditions of the model reaction of vanillin (1h), hydroxylamine hydro-
chloride (2), and ethyl acetoacetate (3a) for the synthesis of 4h in the presence of nano-SiO2–H2SO4.
(Color fgure online)
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F. Ghorbani et al.
0.05 g nano-SiO2–H2SO4 in water at rt for 30 min, the reaction progressed ef-
ciently, giving 4h in 90% isolated yield (the optimized reaction conditions).
After the successful optimization of the reaction conditions, cyclocondensa-
tion reaction of a range of diferent aryl/heteroaryl aldehydes with 2 and 3a was
explored, and the results are given in Table 1. Aromatic aldehydes bearing dif-
ferent electron-donating functional groups were reacted smoothly to form the
desired α,β-unsaturated isoxazol-5(4H)-ones (4a–4p) in good to high yields
(Table 1, entries 11–16). It was also found that when the heterocyclic aldehydes
such as 4-oxo-4H-chromene-3-carbaldehyde, thiophene-2-carboxaldehyde, and
5-methylthiophene-2-carboxaldehyde were used to react with 2 and 3a, the target
heterocyclic products (4q, 4r, and 4s) could be achieved in 86%, 90%, and 91%
yields, respectively (Table 1, entries 17–19). As for steric efect, ortho-substituted
benzaldehydes and 2-hydroxynaphthaldehyde were less efective than those meta-
substituted or para-substituted ones, resulting in the desired products in good to
high yields in 30, 10, and 40 min (Table 1, entries 6, 9, and 16), respectively. As
the example of α,β-unsaturated aldehydes, cinnamaldehyde was also applied in
this 3-CC and gave the 3-methyl-4-(3-phenylallylidene)isoxazol-5(4H)-one (4t)
in yield of 97% (Table 1, entry 20). Nevertheless, no desired heterocyclic prod-
ucts were obtained for aldehydic substrates bearing electron-withdrawing group
on the phenyl ring or aliphatic aldehydes. Then, instead of ethyl acetoacetate (3a),
three β-ketoesters (3b–3d) as substrates were used to perform the 3-CC leading
to the corresponding α,β-unsaturated isoxazol-5(4H)-ones (4u–4aq) in good to
excellent yields (Table 1, entries 17–38).
The structures of the synthesized compounds were confrmed by spectral data.
For example, the 1H NMR spectrum of 4l showed the doublet signals in the regions
at δ 8.45 ppm (d, J=8.7 Hz) and 6.97 (d, J=9.3 Hz) are attributed to aromatic pro-
tons (Ar–H), and the presence of sharp singlet signal at δ 7.65 ppm is attributed
to CH═ between the isoxazol and phenyl rings. The chemical shift for two chloro-
methylene protons (–CH2Cl–) appears as a triplet in the δ 3.91 ppm (J=6.9 Hz),
and a triplet at δ 3.81 ppm (J=6.0 Hz) corresponds to methylene (–CH2–) linking
N bound to the benzene ring. The signal of the protons of methyl group of isoxazol
ring is appeared at δ 2.21 ppm as a sharp singlet signal. From the 13C NMR spec-
trum of 4l, the presence of signals at δ=169.4 and 162.1 ppm corresponds to C=O
and C=N of isoxazol moiety, respectively. The carbon signals of chloromethylene
(–CH2Cl–) and methylene (–CH2–) groups are observed at δ 51.6 and 40.9 ppm,
respectively. The carbon signal of –CH3 is observed at δ=11.3 ppm. The other car-
bons exhibit peaks at their expected values (110.9, 112.0, 122.1, 137.4, 150.5, and
152.1). In comparison, the spectral data of the N-mustard compound 4ad, which is
analogous to 4l, are also shown in Fig. 4.
Furthermore, by the implementation of the reactions in water and using nano-
SiO2–H2SO4 catalyst this protocol ofers advantages, from the green chemistry
point of view, compared to those performed in organic solvents. A literature sur-
vey on some reported approaches for the synthesis of 4-arylidene-3-methylisoxazol-
5(4H)-ones is shown in Table 2. This heteroannulation reaction is preferred in some
aspects, such as relatively shorter reaction times, higher efciency, and a widespread
use of β-ketoester starting materials.
1 3

Facile and expedient synthesis of α,β-unsaturated…
Table 1 Scope of aldehydes and β-ketoesters studied for the synthesis of α,β-unsaturated isoxazol-5(4H)-
a
ones (4a–4aq) catalyzed by nano-SiO2–H2SO4
Entry Structure of
Ar {number of compound}
Time (min) Isolated Mp (°C)
yields
isoxazol-5(4H)-
Observed Reportedb
one
(%)
1
C6H5 {4a}
30
90
138–140 140–142
4a-4t
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-Me-C6H4 {4b}
30
15
5
30
30
5
30
10
10
5
20
60
15
30
40
97
97
98
92
96
98
98
94
89
89
95
91
94
92
91
130–132 135–136
174–176 175–177
210–212 210–211
200–202 199–201
199–201 198–200
218–220 226–227
210–212 213–215
213–215 New
127–129 134–135
171–173 New
178–181 New
188–190 188–191
168–170 194–197
186–187 187–189
198–200 New
4-MeO-C6H4 {4c}
4-HO-C6H4 {4d}
3-HO-C6H4 {4e}
2-HO-C6H4 {4f}
4-(Me)2N-C6H4 {4g}
4-HO-3-MeO-C6H3{4h}
2-HO-3-MeO-C6H3{4i}
3,4-Di-MeO-C6H3{4j}
3,4,5-Tri-MeO-C6H2 {4k}
4-(ClCH2CH2)2N-C6H5 {4l}
4-MeCONH-C6H4 {4m}
4-HO-3,5-di-MeO-C6H2{4n}
3-HO-4-MeO-C6H3{4o}
2-Hydroxynaphthalen-1-yl
{4p}
17
18
19
20
21
4-Oxo-4H-chromen-3-yl {4q} 60
86
90
91
97
91
238–240 242–244
144–146 143–145
170–172 New
177–179 175–177
180–182 183–184
2-Thienyl {4r}
30
35
30
30
5-Methyl-2-thienyl {4s}
C6H5CH=CH {4t}
C6H5 {4u}
4u-4af
22
23
24
25
26
27
28
29
30
31
32
4-Me-C6H4 {4v}
35
20
10
5
30
15
20
10
90
93
98
95
95
92
93
94
93
90
90
136–138 135–137
183–185 175–177
182–184 183–186
182–184 179–180
138–140 141–143
166–168 New
174–176 New
128–130 New
147–149 New
224–226 224–227
147–148 146–148
4-MeO-C6H4 {4w}
4-HO-C6H4 {4x}
4-(Me)2N-C6H4 {4y}
4-HO-3-MeO-C6H3 {4z}
2-HO-3-MeO-C6H3 {4aa}
3,4-Di-MeO-C6H3 {4ab}
3,4,5-Tri-MeO-C6H2 {4ac}
4-(ClCH2CH2)2N-C6H5 {4ad} 30
4-MeCONH-C6H4 {4ae}
2-Thienyl {4af}
60
30
1 3

F. Ghorbani et al.
Table 1 (continued)
Entry Structure of
isoxazol-5(4H)-
one
Ar {number of compound}
C6H5 {4ag}
Time (min) Isolated Mp (°C)
yields
(%)
Observed Reportedb
33
40
90
210–212 213–215
4ag-4al
34
4-Me-C6H4 {4ah}
4-MeO-C6H4 {4ai}
4-HO-C6H4 {4aj}
4-(Me)2N-C6H4 {4ak}
40
30
10
10
88
90
95
91
90
96
195–196 195–196
167–169 168–170
208–210 209–211
194–196 195–197
131–133 New
35
36
37
38
39
4-(ClCH2CH2)2N-C6H5 {4al} 25
4-HO-C6H4 {4am}
7
151–153 New
4am-4aq
40
4-(Me)2N-C6H4 {4an}
3,4-Di-MeO-C6H3 {4ao}
3,4,5-Tri-MeO-C6H2 {4ap}
5
20
8
90
90
90
97
118–120 New
127–129 New
41
42
43
80–82
New
4-(ClCH2CH2)2N-C6H5 {4aq} 35
179–181 New
aReactions were carried out using aldehydes (1, 1 mmol), hydroxylamine hydrochloride (2, 1 mmol),
β-ketoesters (3a–3d, 1 mmol), nano-SiO2–H2SO4 (0.05 g), water (5 mL) at room temperature
bMelting points are listed in Refs. [34–66]
Fig. 4 1H and 13C NMR chemical shifts of heterocyclic compound 4ad
Based on the previous literature [34–66], the proposed mechanism for this annu-
lation is outlined in Scheme 2. Treatment of hydroxylamine hydrochloride with
β-ketoesters (3a–3d) gives the corresponding oxime derivatives C. The aldehydes
activated with nano-SiO2–H2SO4 are converted to oxime arylidene intermediates (F)
via the Knoevenagel reaction with oxime intermediates (D) and dehydration. The
desired heterocyclic compounds (4a–4aq) were then obtained through the intramo-
lecular O-attack cyclization and deethanolization.
Control experiments were performed under the optimized reaction conditions to
investigate insights into the reaction mechanism (Scheme 3). The frst reaction (I)
1 3

Facile and expedient synthesis of α,β-unsaturated…
1 3

F. Ghorbani et al.
Scheme 2 Proposed reaction mechanism for the synthesis of 4-arylidene-isoxazol-5(4H)-ones (4a–4aq)
failed, and staining materials on TLC remained unchanged after 30 min. The subse-
quent reaction (II) proceeded well, and the TLC indicated that the starting materials
had disappeared and a new compound had formed. The white powder was obtained
and analyzed by physical data, FT-IR spectrum, and elemental analysis. It was possi-
ble to form two reaction intermediates 6 and 7. Studies show that reaction intermediate
7 was formed. In the IR spectrum, the peaks observed in regions 3458 and 1692 cm−1
indicate the formation of the oxime intermediate. The peak in the region of 3458 cm−1
confrms the hydroxyl functional group in the intermediate. Also, the ester carbonyl
Scheme 3 Control experiments to investigate the proposed reaction mechanism
1 3

Facile and expedient synthesis of α,β-unsaturated…
OH
H
3CO
fresh
run
O
30
30
98%
98%
1h
min,
min,
CHO
+
NH
2OH.HCl
2
OEt
3a
1
O
CH3
H
3CO
HO
run
run
2
N
O
30
30
96%
90%
min,
min,
O
4h
3
Fig. 5 Reusability of the catalyst
group appeared in the region 1692 cm−1 due to the hydrogen bond [44]. Also, ele-
mental analysis data show that the oxime intermediate is formed, and no isoxazolone
ring intermediate 6 is formed. These results showed that the oxime intermediates are
involved in this 3-CC. Although the exact mechanism of the reaction unclear at this
time based on the recent literature [44–59] and above-mentioned control investigates,
the proposed mechanism may be accepted with probability.
The recyclability of the catalyst was investigated in the model reaction under
optimized conditions (Fig. 5). After the completion of reaction, the solid product
was dissolved in hot ethanol and fltered of. The catalyst remained on flter paper
and heterocyclic compound in hot fltered solution. The recovered catalyst was
reused three times without any signifcant decrease in the yield of the corresponding
heterocyclic compound.
Conclusions
In summary, an efcient, environmentally benign, and green approach for the syn-
thesis of α,β-unsaturated isoxazol-5(4H)-ones from readily accessible precursors has
been illustrated. The corresponding heterocyclic products were produced at room
temperature in high yields and shorter reaction times. In this study, the structure of
the newly synthesized α,β-unsaturated isoxazol-5(4H)-ones was confrmed on the
basis of spectral data. This 3-CC approach has several additional advantages, includ-
ing easy product isolation, recycling of the catalyst, minimization of waste, simplic-
ity of operation, broad β-ketoester substrate scope, and easy work-up.
Acknowledgements The authors are thankful to Damghan University Research Council for fnancial sup-
port of this study.
1 3

F. Ghorbani et al.
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Afliations
Fatemeh Ghorbani1 · Hamzeh Kiyani1 · Seied Ali Pourmousavi1
*
Hamzeh Kiyani
hkiyani@du.ac.ir
1
School of Chemistry, Damghan University, Damghan 36716-41167, Iran
1 3