Copper-catalysed synthesis of 3,5-disubstituted isoxazoles enabled by pyridinyl benzimidazol (PBI) as a bidentate N-chelating ligand under mild conditions

Article abstract of DOI:10.1007/s13738-017-1280-0

In this paper, we introduced pyridinyl benzimidazol (PBI) as an easy-to-handle and bidentate N-chelating ligand that promote clean synthesis of 3,5-disubstituted isoxazoles in the presence of copper acetate as catalyst. This catalytic approach initiates with the hydroxyamination of aldehydes followed by chlorination and then generation of nitrile oxide which subsequently undergoes click-type [3?+?2]-dipolar cycloaddition with alkynes to give isoxazoles. This method provides an alternative green process to construct isoxazole derivatives.

Full text of DOI:10.1007/s13738-017-1280-0

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-017-1280-0
ORIGINAL PAPER
Copper‑catalysed synthesis of 3,5‑disubstituted isoxazoles enabled
by pyridinyl benzimidazol (PBI) as a bidentate N‑chelating ligand
under mild conditions
Reza Khalifeh1 · Fatemeh Shahriarpour1 · Hashem Sharghi2 · Mahdi Aberi2
Received: 10 May 2017 / Accepted: 23 December 2017
© Iranian Chemical Society 2018
Abstract
In this paper, we introduced pyridinyl benzimidazol (PBI) as an easy-to-handle and bidentate N-chelating ligand that promote
clean synthesis of 3,5-disubstituted isoxazoles in the presence of copper acetate as catalyst. This catalytic approach initiates
with the hydroxyamination of aldehydes followed by chlorination and then generation of nitrile oxide which subsequently
undergoes click-type [3 + 2]-dipolar cycloaddition with alkynes to give isoxazoles. This method provides an alternative
green process to construct isoxazole derivatives.
Keywords Isoxazole derivatives · Pyridinyl benzimidazol (PBI) · Bidentate ligand · Cycloaddition reaction
Introduction
Regarding their prevalence, numerous research studies
have been carried out on the synthesis of isoxazoles and their
derivatives [12, 13].
Design and efcient synthesis of biologically active mol-
ecules have emerged as a tremendous challenge in medicinal
chemistry.
The main strategy that has been employed generally to
prepare isoxazole derivatives is the [3 + 2] dipolar cycload-
dition of alkenes or alkynes with nitrile oxides [14–17].
The nitrile oxide 1,3-dipole is generated in situ from the
corresponding primary nitroalkanes [18, 19] and hydroxi-
moyl chlorides [20].
Heterocyclic compounds are frequently found in natural
products and functional material. Among the several het-
erocycles, isoxazole derivatives are attractive frameworks
that present in many bioactive compounds including anti-
infective, antitumor, cardiovascular [1–3], antituberculosis
[4], anti-infammatory [5], antibacterial [6], anti-HIV [7],
anticancer [8] and nervous system agents [1–3].
They are also core structures of some pesticides and
insecticides that have agrochemical properties including
herbicidal and soil fungicidal activity [9].
The reactions of hydroxylamine with 1,3-dicarbonyl com-
pounds [21], α,β-unsaturated carbonyl compounds [22] and
α,β-unsaturated nitriles have also been reported [23]. Addi-
tionally, the alternative approaches such as the reaction of
an oxime-derived dianion with an ester [24] or amide [25]
also provide isoxazoles.
Isoxazoles are also indispensable as they participate as
intermediates in the synthesis of numerous natural products
[10, 11].
Ring systems which contain nitrogen atom have been
widely used as ligands in organometallic chemistry.
Benzimidazole as a typical heterocyclic ligand with nitro-
gen as the donor atom is frequently used in organometallic
chemistry. In particular, 2-(2-pyridinyl)-1H-benzimidazole
can be described as donor ligand because two nitrogen atoms
of the benzimidazole and pyridine moieties participate in
coordination. Organometallic complexes containing benzi-
midazolic ligands are efectively used in coordination chem-
istry [26–28].
* Reza Khalifeh
khalifeh@sutech.ac.ir
1
2
Department of Chemistry, Shiraz University of Technology,
Shiraz 71555-313, Iran
Some of these complexes have been applied as highly
active catalysts for organic reactions such as N-arylation of
indoles [29] and olefn epoxidation [30].
Department of Chemistry, Shiraz University, Shiraz 71454,
Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
As a continuation of our previous work [31–39] on the
preparation of some new heterocyclic compounds, herein we
report our recent research into the green and three-step regi-
oselective synthesis of isoxazole derivatives from aldehydes
and alkynes, under a mild condition in water, whereupon
nitrile oxide intermediates are generated in situ and further
reacted without isolation.
for starting the reaction, the mixture is heated to 45 °C. The
remaining 8.2 mmol of NCS was added in small portions
while keeping the temperature below 35 °C (below 60 °C
for electron-defcient oximes). The mixture was then stirred
at room temperature for 1 h and quenched with water and
extracted with chloroform (3 × 10 mL) to give the imidoyl
chloride products in 72–93% yield.
General procedure for the synthesis of isoxazoles
from nitrile oxides and alkynes
Experimental section
Instrumentation, analyses and starting material
To a stirred solution of imidoyl chloride (1 mmol) and
alkyne (1 mmol) in H2O (5 mL), pyridinyl benzimidazole
(1 mol%), copper(II)acetate (1 mol%) and K2CO3 (2 mmol)
were added. The resulting solution was stirred at room tem-
perature for 3 h. After the completion of the reaction, it was
diluted with water, and the solid of-white isoxazole product
was fltered of.
NMR spectra were recorded on a Bruker Avance DPX-250
(1H NMR at 250 MHz and 13C NMR at 62.5 MHz) spec-
trometer in pure deuterated solvents with TMS as an internal
standard. IR spectra were obtained using a Shimadzu FT-IR
8300 spectrophotometer. Mass spectra were determined on
a Shimadzu GCMS-QP 1000 EX instruments at 70 or 20 eV.
Elemental analyses were performed with a Thermo Finni-
gan CHNS-O 1112 series analyser. Melting points deter-
mined in open capillary tubes in a Buchi-535 circulating
oil melting point apparatus. The purity determination of the
substrates and reaction monitoring were accomplished by
TLC on silica gel PolyGram SILG/UV 254 plates. Column
chromatography was carried out on short columns of silica
gel 60 (70–230 mesh) in glass columns (2–3 cm diameter)
using 15–30 g of silica gel per g crude mixture. Chemical
materials were purchased from Fluka, Aldrich and Merck.
The used activated carbon was also purchased from Merck
(Atr. No. 9631, 0.3–0.05 mm).
3‑(4‑Chlorophenyl)‑5‑phenylisoxazole (1) White solid, m.p:
177–178 °C. IR (KBr): 3114 (m), 1612 (s), 1489 (s), 1446
(s), 1425 (s), 1383 (s), 1093 (s), 1015 (s), 950 (s), 838 (s),
815 (s), 760 (s), 693 (s), 517 (s) cm−1. 1H NMR (250 MHz,
CDCl3): δ = 6. 80 (s, 1H), 7.44–7.52 (m, 5H), 7.79–7.88 (m,
4H). 13C NMR (62.5 MHz, CDCl3): δ = 97.3, 125.8, 127.2,
128.0, 128.2, 129.0, 129.2, 130.3, 136.0, 161.8, 168.3.
Mas m/z (%) 257 (M++2, 2.8), 256 (M++1, 7.5), 255 (M+,
10.5), 105 (100.0), 77 (41.1). Anal. calcd. for C15H10ClNO
(255.699): C 70.46 H 3.94; found: C 79.81, H 4.97.
3,5‑Diphenylisoxazole (2) White solid, m.p: 121 °C. IR
(KBr): 3114 (m), 3049 (m), 1593 (s), 1573 (s), 1463 (s),
1461 (s), 1402 (s), 950 (s), 820 (s), 764 (s), 700 (s), 555
(s), 529 (m) cm−1. 1H NMR (250 MHz, CDCl3): δ = 6.83
(s, 1H), 7.43–7.53 (m, 6H), 7.83–7.90 (m, 4H). 13C NMR
(62.5 MHz, CDCl3): δ = 97.5, 125.8, 126.8, 128.3, 128.7,
128.9, 129.0, 130.0, 130.2, 130.6, 131.0, 163.0, 170.4. Mas
m/z (%) 223 (M++2, 3.5), 222 (M++1, 15.2), 221 (M+,
20.0), 178 (25.6), 144 (12.7), 105 (100.0), 77 (72.5), 51
(22.3). Anal. calcd. for C15H11NO (221.254): C 81.43 H
5.01; found: C 79.81, H 4.97.
General procedure
General procedure for the preparation of imidoyl chlorides
10 mmol of aldehyde was dissolved in 10 mL of H2O/EtOH
(v/v) 1/1) mixture by stirring in a 100-mL round-bottomed
fask. The solution was cooled to 0 °C, and 10 mmol of
hydroxylamine hydrochloride was added to this solution.
Then 25 mmol of NaOH as a 50% solution in water was
added dropwise. The reaction mixture is allowed to warm
slowly to room temperature and stirred for 1 h. The solution
was extracted with chloroform, and the aqueous phase was
acidifed to pH 6 by adding concentrated HCl while keeping
the temperature below 30 °C and extracted with chloroform
to give the oxime products in 90–97% yield. For chlorina-
tion of oxime, 1.8 mmol of N-chlorosuccinimide (NCS) was
added in one portion to a solution of 10 mmol of oxime in
DMF (10 mL). A slight increase in the reaction temperature
shows the beginning of the reaction. A small amount of HCl
gas can be bubbled through the solution when the reaction
does not start. In the case of the electron-defcient oximes
3‑(4‑Methoxyphenyl)‑5‑phenylisoxazole (3) White solid,
m.p: 120 °C. IR (KBr): 3110 (m), 2942 (m), 1613 (s), 1572
(s), 1529 (s), 1492 (s), 1447 (s), 1434 (s), 1295 (s), 1250 (s),
1178 (s), 1027 (s), 836 (s), 817 (s), 761 (s), 691 (s), 537 (s)
cm−1. 1H NMR (250 MHz, CDCl3): δ = 3.88 (s, 3H), 6.78
(s, 1H), 7.00 (dd, 2H, J1 = 6.8 Hz, J2 = 2.5 Hz), 7.41–7.53
(m, 3H), 7.74–7.89 (m, 4H). 13C NMR (62.5 MHz, CDCl3):
δ = 55.3, 97.3, 112.1, 114.3, 121.6, 125.8, 126.4, 127.5,
128.2, 128.6, 129.0, 130.1, 161.0, 162.6, 170.1. Mas m/z (%)
253 (M++2, 2.0), 252 (M++1, 12.9), 251 (M+, 16.1), 105
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Journal of the Iranian Chemical Society
(100.0), 77 (56.0). Anal. calcd. for C16H13NO2 (251.280): C
76.48 H 5.21; found: C 79.81, H 4.97.
(%) 265 (M++1, 4.8), 264 (M+, 10.7), 236 (19.4), 152
(18.7), 123 (24.6), 97 (60.3), 57 (100.0). Anal. calcd. for
C17H16N2O (264.322): C 77.25 H 6.10; found: C 79.81, H
4.97.
3‑(4‑Isopropylphenyl)‑5‑phenylisoxazole (4) White solid,
m.p: 111 °C. IR (KBr): 3111 (m), 2966 (s), 2962 (s), 1615
(s), 1567 (s), 1492 (s), 1447 (s), 1431 (s), 1387 (s), 1056
(s), 948 (s), 839 (s), 820 (s), 768 (s), 694 (s), 555 (s) cm−1.
1H NMR (250 MHz, CDCl3): δ = 1.29 (d, 6H, J = 9.6 Hz),
2.92–3.03 (m, 1H), 6.82 (s, 1H), 7.35 (d, 2H, J = 8.3 Hz),
7.44–7.52 (m, 3H), 7.80 (d, 2H, J = 8.6 Hz), 7.82–7.87 (m,
2H). 13C NMR (62.5 MHz, CDCl3): δ = 23.9, 34.0, 97.4,
125.8, 126.6, 126.8, 127.0, 127.5, 129.0, 130.1, 151.0,
162.9, 170.2. Mas m/z (%) 265 (M++2, 5.3), 264 (M++1,
24.1), 263 (M+, 38.5), 248 (40.6), 186 (2.1), 105 (100.0),
77 (41.1). Anal. calcd. for C18H17NO (263.334): C 82.10 H
6.51; found: C 79.81, H 4.97.
Ethyl 4‑(5‑phenyl‑3‑isoxazolyl)benzoate (8) White solid,
m.p: 138 °C. IR (KBr): 2988 (m), 1735 (s), 1449 (s), 1295
(s), 1270 (s), 1126 (s), 1109 (s), 1025 (s), 950 (s), 864 (s),
774 (s), 759 (s), 688 (s), 679 (s) cm −1. 1H NMR (250 MHz,
CDCl3): δ = 1.20 (trp, 3H, J = 7.1 Hz), 4.18 (qr, 2H,
J = 7.9 Hz), 6.64 (s, 1H), 7.23–7.29 (m, 3H), 7.60–7.64
(m, 2H), 7.71 (d, 2H, J = 7.5 Hz), 7.92 (d, 2H, J = 6.7 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 14.3, 61.2, 97.5, 125.8,
126.7, 127.2, 129.0, 130.1, 130.4, 131.7, 133.2, 162.2,
166.0, 170.8. Mas m/z (%) 295 (M++2, 5.5), 294 (M++1,
26.8), 293 (M+, 34.0), 248 (17.5), 105 (100.0), 77 (26.6).
Anal. calcd. for C18H15NO3 (293.317): C 73.71 H 5.15;
found: C 79.81, H 4.97.
3‑(4‑Methylphenyl)‑5‑phenylisoxazole (5) White solid, m.p:
131 °C. IR (KBr): 3117 (m), 1614 (s), 1570 (s), 1492 (s),
1447 (s), 1426 (s), 1188 (m), 1117 (m), 1075 (s), 947 (s),
830 (s), 765 (s), 684 (s), 524 (s) cm−1. 1H NMR (250 MHz,
CDCl3): δ = 2.41 (s, 3H), 6.80 (s, 1H), 7.24–7.30 (m, 2H),
7.45–7.47 (m, 2H), 7.49 (t, 2H, J = 1.9 Hz), 7.77 (dd, 1H,
J1 = 8.2 Hz, J2 = 2.3 Hz), 7.80–7.87 (m, 2H). 13C NMR
(62.5 MHz, CDCl3): δ = 21.4, 97.4, 125.8, 126.3, 126.7,
127.5, 129.0, 129.6, 130.1, 140.1, 162.9, 170.2. Mas m/z (%)
237 (M++2, 3.2), 236 (M++1, 13.1), 235 (M+, 19.3), 158
(10.6), 105 (100.0), 77 (53.8). Anal. calcd. for C16H13NO
(235.281): C 81.68 H 5.57; found: C 79.81, H 4.97.
3‑(2,4‑Dichlorophenyl)‑5‑phenylisoxazole (9) White solid,
m.p: 96 °C. IR (KBr): 3162 (w), 3058 (w), 1598 (s), 1553
(s), 1487 (s), 1450 (s), 1400 (s), 1364 (s), 1106 (s), 1055
(s), 954 (s), 934 (s), 865 (s), 821 (s), 750 (s), 680 (s), 539
(s), 456 (s) cm−1. 1H NMR (250 MHz, CDCl3): δ = 6.98 (s,
1H), 7.36 (dd, 1H, J1 = 10 Hz, J2 = 2 Hz), 7.45–7.51 (m,
3H), 7.53 (d, 1H, J = 2 Hz), 7.75 (d, 1H, J = 8.5 Hz), 7.81–
7.99 (m, 2H). 13C NMR (62.5 MHz, CDCl3): δ = 100.5,
125.8, 127.5, 127.7, 128.6, 129.0, 130.9, 131.7, 132.7,
133.6, 136.2, 160.6, 170.0. Mas m/z (%) 292 (M++2, 3.3),
291(M++1, 5.7), 290 (M+, 3.7), 289 (11.3), 105 (100.0), 77
(44.4). Anal. calcd. for C15H9Cl2NO (290.143): C 62.09 H
3.13; found: C 79.81, H 4.97.
3‑(3,5‑Dimethoxyphenyl)‑5‑phenylisoxazole (6) White solid,
m.p: 110 °C. IR (KBr): 3005 (m), 2940 (m), 1612 (s), 1572
(s), 1526 (s), 1493 (s), 1460 (s), 1430 (s), 1257 (s), 1200 (s),
1171 (s), 1143 (s), 1022 (s), 947 (s), 861 (s), 760 (s), 690 (s),
cm−1. 1H NMR (250 MHz, CDCl3): δ = 3.93 (s, 3H), 3.96 (s,
3H), 6.79 (s, 1H), 6.94 (dd, 1H, J1 = 8.3 Hz, J2 = 2.6 Hz),
7.35 (dd, 1H, J1 = 8.3 Hz, J2 = 1.9 Hz), (m, 4H), 7.81–7.86
(m, 2H). 13C NMR (62.5 MHz, CDCl3): δ = 56.0, 97.3,
109.2, 110.5, 119.9, 125.8, 127.4, 129.0, 130.1, 150.6,
162.7, 170.2. Mas m/z (%) 283 (M++2, 6.7), 282 (M++1,
44.1), 281 (M+, 74.9), 204 (11.4), 179 (13.2), 105 (100.0),
77 (37.2). Anal. calcd. for C17H15NO3 (281.306): C 72.58 H
5.37; found: C 79.81, H 4.97.
3‑(4‑Nitrophenyl)‑5‑phenylisoxazole (10) White solid, m.p:
222 °C. IR (KBr): 3114 (m), 1572 (m), 1530 (s), 1489 (m),
1449 (s), 1356 (s), 1344 (s), 1114 (m), 951 (m), 863 (s), 814
(s), 772 (s), 695(s) cm−1. 1H NMR (250 MHz, DMSO-d6):
δ = 7.55–7.57 (m, 3H), 7.73 (s, 1H), 7.90–7.92 (m, 2H),
8.18 (d, 2H, J = 6.5 Hz), 8.39 (d, 2H, J = 6.5 Hz). 13C NMR
(62.5 MHz, DMSO-d6): δ = 97.3, 115.6, 124.3, 125.7, 126.5,
127.7, 128.6, 129.0, 130.1, 135.3, 148.6, 161.1, 171.5. Mas
m/z (%) 268 (M++2, 2.8), 267 (M++1, 10.5), 266 (M+,
13.7), 105 (100.0), 77 (48.8). Anal. calcd. for C15H10N2O3
(266.252): C 67.67 H 3.79; found: C 79.81, H 4.97.
N,N‑dimethyl‑4‑(5‑phenyl‑3‑isoxazolyl)aniline (7) White
solid, m.p: 127–128 °C. IR (KBr): 3399 (m), 3217 (m), 2949
(m), 2839 (m), 1740 (s), 1609 (s), 1506 (s), 1412 (s), 1376
(s), 1338 (s), 1163 (s), 1056 (m), 950 (s), 777 (m), 681 (m),
5‑Phenyl‑3‑(2‑thienyl)isoxazole (11) White solid, m.p:
119–120 °C. IR (KBr): 3117 (m), 1615 (m), 1576 (s), 1489
(m), 1446 (s), 1425 (s), 1344 (m), 1071 (m), 949 (s), 916
(s), 851 (s), 755 (s), 750 (s), 745 (s), 667 (s), 614 (s), 517
(m) cm −1. 1H NMR (250 MHz, CDCl3): δ = 6.68 (s, 1H),
7.36–7.42 (m, 4H), 7.51 (dd, 1H, J1 = 1.1 Hz, J2 = 5.0 Hz),
7.71 (dd, 1H, J1 = 1.2 Hz, J2 = 2.9 Hz), 7.74–7.78 (m, 2H).
13C NMR (62.5 MHz, CDCl3): δ = 97.8, 119.8, 124.6, 125.8,
1
595 (s) cm −1. H NMR (250 MHz, CDCl3): δ = 2.82 (s,
6H), 5.93 (s, 1H), 6.95 (dd, 2H, J1 = 1.8 Hz, J2 = 8.5 Hz),
7.55–7.56 (m, 2H), 7.59–7.61 (m, 2H), 7.73–7.75 (m, 3H).
13C NMR (62.5 MHz, CDCl3): δ = 43.2, 97.8, 119.1, 126.7,
126.9, 127.0, 129.5, 130.3, 139.9, 168.0, 177.9. Mas m/z
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Journal of the Iranian Chemical Society
126.0, 129.0, 130.2, 134.5, 145.5, 158.8, 170.1. Mas m/z (%)
229 (M++2, 2.5), 228 (M++1, 13.3), 227 (M+, 13.5), 105
(100.0), 77 (56.5). Anal. calcd. for C13H9NOS (227.283): C
68.70, H 3.99; found: C 79.81, H 4.97.
2H, J1 = 6.7 Hz, J2 = 1.7 Hz), 7.71 (dd, 2H, J1 = 6.7 Hz,
J2 = 1.7 Hz), 7.87–7.97 (m, 3H), 8.10 (d, 1H, J = 1.5 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 33.6, 102.0, 121.3, 125.6,
128.1, 129.2, 134.7, 135.3, 136.2, 160.6, 162.9, 166.1. Mas
m/z (%) 376 (M++2, 6.0), 375 (M++1, 9.9), 374 (M+, 14.8),
178 (100.0), 150 (33.9), 111 (16.4), 77 (16.6). Anal. calcd.
for C17H11ClN2O4S (374.799): C 54.48, H 2.96; found: C
79.81, H 4.97.
5‑(Bromomethyl)‑3‑(4‑chlorophenyl)isoxazole (12) White
solid, m.p: 116 °C. IR (KBr): 3135 (m), 3039 (m), 2979
(m), 1606 (s), 1429 (s), 1290 (s), 1228 (s), 1100 (s), 1016
(s), 934 (s), 834 (s), 811 (s), 666 (s), 569 (s), 498 (s) cm
−1. 1H NMR (250 MHz, CDCl3): δ = 4.51 (s, 2H), 6.59 (s,
1H),7.42 (dd, 2H, J1 = 6.6 Hz, J2 = 2 Hz), 7.71 (dd, 2H,
J1 = 9.0 Hz, J2 = 2.4 Hz). 13C NMR (62.5 MHz, CDCl3):
δ = 18.5, 101.8, 127.0, 128.0, 129.3, 136.3, 161.8, 168.3.
Mas m/z (%) 274 (M++2, 8.1), 273 (M++1, 15.5), 272 (M+,
11.3), 178 (100.0), 150 (30.6), 127 (13.4), 111 (35.7), 75
(38.2), 51 (13.2). Anal. calcd. for C10H7BrClNO (272.525):
C 44.07 H 2.59; found: C 79.81, H 4.97.
[3‑(4‑Chlorophenyl)‑5‑isoxazolyl]methanol (16) White solid,
m.p: 96 °C. IR (KBr): 3305 (s), 3147 (w), 2943 (w), 1608
(s), 1572 (m), 1511 (m), 1456 (s), 1440 (s), 1373 (s), 1275
(w), 1161 (w), 1095 (s), 1082 (s), 1061 (s), 1013 (m), 925
1
(s), 836 (s), 829 (s), 800 (s), 684 (m), 517 (m) cm−1. H
NMR (250 MHz, CDCl3): δ = 2.9 (s, 1H), 4.80 (s, 2H),
6.52 (s, 1H), 7.40 (dd, 2H, J1 = 6.7 Hz, J2 = 1.8 Hz), 7.69
(dd, 2H, J1 = 6.7 Hz, J2 = 1.9 Hz). 13C NMR (62.5 MHz,
CDCl3): δ = 56.4, 99.9, 127.2, 128.0, 129.2, 136.2, 161.5,
172.3. Mas m/z (%) 211 (M++2, 10.1), 210 (M++1, 25.7),
209 (M+, 26.1), 178 (100.0), 150 (54.8), 111 (39.7), 75
(44.3) 50 (13.8). Anal. calcd. for C10H8ClNO2 (209.629): C
57.30 H 3.85; found: C 79.81, H 4.97.
5‑(Chloromethyl)‑3‑(4‑chlorophenyl)isoxazole (13) White
solid, m.p: 105 °C. IR (KBr): 3140 (m), 3020 (m), 2973
(m), 1610 (s), 1510 (s), 1440 (s), 1275 (s), 1175 (s),
1090 (s), 1015 (s), 939 (s), 885 (s), 824 (s), 812 (s), 709
1
(s), 677 (s), 500 (s) cm−1. H NMR (250 MHz, CDCl3):
δ = 4.64 (s, 2H), 6.61 (s, 1H), 7.44 (dd, 2H, J1 = 6.6 Hz,
2‑[3‑(4‑Chlorophenyl)‑5‑isoxazolyl]‑2‑propanol (17) White
solid, m.p: 96–98 °C. IR (KBr): 3350 (m), 2993 (m), 1601
(s), 1568 (s), 1509 (m), 1456 (m), 1442 (s), 1405 (s), 1264
(s), 1223 (s), 1190 (s), 1090 (s), 1014 (s), 967 (s), 925 (s),
802 (s), 623 (s) cm −1. 1H NMR (250 MHz, CDCl3): δ = 1.64
(s, 6H), 2.66 (s, 1H), 6.44 (s, 1H), 7.40 (dd, 2H, J1 = 1.8 Hz,
J2 = 1.9 Hz), 7.73 (dd, 2H, J1 = 6.5 Hz, J2 = 1.9 Hz). 13
C
NMR (62.5 MHz, CDCl3): δ = 34.4, 100.3, 101.7, 127.0,
128.0, 129.2, 136.3, 161.7, 168.3. Mas m/z (%) 230 (M++2,
12.3), 229 (M++1, 18.6), 228 (M+, 14.9), 227 (18.9), 178
(100.0), 150 (46.1), 111 (29.3), 75 (37.2), 51 (12.6). Anal.
calcd. for C10H7Cl2NO (228.074): C 52.66 H 3.09; found:
C 79.81, H 2.95.
J2 = 4.8 Hz), 7.70 (dd, 2H, J1 = 1.8 Hz, J2 = 8.5 Hz). 13
C
NMR (62.5 MHz, CDCl3): δ = 29.0, 69.2, 97.3, 127.4,
128.0, 129.2, 136.0, 161.3, 178.8. Mas m/z (%) 240 (M++2,
5.4), 239 (M++1, 8.6), 238 (M+, 16.1), 222 (28.0), 178
(47.0), 152 (35.8), 111 (20.3), 85 (22.4), 59 (100.0). Anal.
calcd. for C12H12ClNO2 (237.682): C 60.64, H 5.09; found:
C 79.81, H 4.97.
3‑(4‑Chlorophenyl)‑5‑[(4‑methylphenoxy)methyl]isoxazole
(14) White solid, m.p: 122 °C. IR (KBr): 3130 (m), 2921
(m), 1617 (s), 1600 (s), 1500 (s), 1420 (s), 1373 (s), 1294
(s), 1248 (s), 1182 (s), 1100 (s), 1013 (s), 949 (s), 922 (s),
1
834 (s), 820 (s), 786 (s), 512 (s), 492 (s) cm−1. H NMR
(250 MHz, CDCl3): δ = 2.30 (s, 3H), 5.15 (s, 2H), 6.61 (s,
1H), 6.89 (d, 2H, J1 = 8.6 Hz), 7.12 (d, 2H, J1 = 8.6 Hz),
7.37–7.45 (m, 2H), 7.74 (d, 2H, J1 = 8.5 Hz). 13C NMR
(62.5 MHz, CDCl3): δ = 20.5, 61.5, 101.1, 114.6, 127.3,
128.1, 129.5, 130.1, 131.3, 136.1, 155.7, 161.5, 169.1. Mas
m/z (%) 301 (M++2, 13.0), 300 (M++1, 21.7), 299 (M+,
26.5), 192 (46.4), 139 (15.3), 107 (100.0), 77 (39.5). Anal.
calcd. for C17H14ClNO2 (299.751): C 68.12 H 4.71; found:
C 79.81, H 4.97.
Result and discussion
2-(2-Pyridinyl)-1H-benzimidazole (PBI) was prepared from
the reaction between 2-pyridylaldehyde and 1,2-phenylene-
diamine in the presence of copper nanoparticles on activated
carbon (Cu/C) as a heterogeneous catalyst [34].
We then examined the efect of the nitrogen-based ligand
for the synthesis of isoxazoles in the reaction of aldehydes
with alkynes using Cu(OAc)2 as a catalyst without any
reducing agent.
2‑{[3‑(4‑Chlorophenyl)‑5‑isoxazolyl]methyl}‑1,2‑benzisothia‑
zol‑3(2H)‑one 1,1‑dioxide (15) White solid, m.p: 186 °C. IR
(KBr): 3482 (m), 3141 (w), 3093 (w), 2923 (w), 1750 (s),
1611 (m), 1431 (s), 1331 (s), 1302 (s), 1268 (s), 1185 (s),
1090 (m), 923 (m), 754 (s), 588 (s), 513 (s) cm−1. 1H NMR
(250 MHz, CDCl3): δ = 5.08 (s, 2H), 6.66 (s, 1H), 7.40 (dd,
Firstly, a three-step approach to the synthesis of isox-
azoles has been examined: (1) preparation of the aldoxi-
mes, (2) formation of the imidoyl chlorides and (3) [3 + 2]
cycloaddition reactions (Scheme 1). The nitrile oxides
required for this methodology are readily prepared from
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Journal of the Iranian Chemical Society
Scheme 1 3,5-Disubstituted
isoxazoles prepared from
aldehydes
aldehydes. To this end, an aldehyde is frst converted to the
corresponding aldoxime via reaction with hydroxylamine
chloride and sodium hydroxide in an ethanol/water mixture
at room temperature. The aldoxime is transformed to the
corresponding imidoyl chlorides using N-chlorosuccinimide
in DMF. Finally, alkyne reacted with nitrile oxide, which
was generated in situ by dehydrohalogenation of imidoyl
chloride in the presence of catalytic amount of PBI/cop-
per (II) acetate, an appropriate base and solvent to afording
isoxazoles.
In the beginning, the 4-chlorobenzaldehyde was chosen
as a selected substrate for the synthesis of imidoyl chloride.
Table 1 Optimization of the reaction conditions
Entry
Catalyst
Condition
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
Cu(OAc)2/PBI
CuI/PBI
CH2Cl2/K2CO3
DMSO/K2CO3
Acetone/K2CO3
THF/K2CO3
CH3CN/K2CO3
Dioxane/K2CO3
PEG 300/K2CO3
EtOH/K2CO3
H2O/K2CO3
H2O/K3PO4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
18
12
16
41
53
65
79
90
95
9
68
15
83
0
95
76
95
80
83
79
71
75
0
9
10
11
12
13
14
15a
16b
17c
18d
19
20
21
22
23
H2O/NaHCO3
H2O/Cs2CO3
H2O/Et3N
H2O/NaOH
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
H2O/K2CO3
CuBr/PBI
CuCl/PBI
Cu(OAc)2
–
Reaction conditions: 4-chloro-N-hydroxybenzenecarboximidoyl chloride (1 mmol), phenyl acetylene (1 mmol), Cu(II)/PBI (1 mol%), K2CO3
(2 mmol)
aK2CO3 (3 mmol)
bK2CO3 (1 mmol)
cCu(OAc)2/PBI (2 mol%)
dCu(OAc)2/PBI (0.5 mol%)
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Journal of the Iranian Chemical Society
Table 2 Substrate scope for the synthesis of isoxazole derivatives
Yield
(%)a
Entry
Aldhyde
Alkyne
Product
1
95
90
90
1
2
3
2
3
4
85
4
5
5
87
6
7
90
90
6
7
CHO
8
9
80
89
8
CO2Et
9
10
11
80
92
10
11
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Journal of the Iranian Chemical Society
Table 2 (continued)
12
13
14
89
88
82
12
13
14
15
78
15
16
16
17
75
81
17
Reaction conditions: aldehyde (1 mmol), alkyne (1 mmol), Cu(II)/PBI (1 mol%), K2CO3 (2 mmol) a) K2CO3 (3 mmol)
aIsolated yields
In order to optimize the reaction conditions for the isoxa-
zole synthesis, a model reaction using 4-chloro-N-hydroxy-
benzenecarboximidoyl chloride (prepared in situ from cor-
responding aldehyde) and phenyl acetylene was screened in
detail (Table 1).
The best result was observed under 1 mol% of Cu(II)/
PBI catalysis in H2O at room temperature in the presence
of 2 mmol K2CO3 (Table 1, entry 9).
Next, the infuence of the base on the result of the
model reaction was studied. For this purpose, equimolar
amounts of 4-chloro-N-hydroxybenzenecarboximidoyl
chloride and phenyl acetylene were reacted in H2O with
a twofold excess of K3PO4, NaHCO3, NaOH, Cs2CO3
and Et3N, respectively. With K3PO4 as the base the yield
dropped to 9% (Table 1, entry 10). The yields obtained
with NaHCO3, Cs2CO3 and Et3N amounted to 68, 15 and
83%, respectively (Table 1, entries 11–13). Conversely,
the extent of the [3 + 2] cycloaddition reaction between
alkynes and nitrile oxides dramatically fell when NaOH
was used as a base in H2O (Table 1, entry 14). Increasing
the stoichiometry of K2CO3 to 3 equiv had shown no use-
ful improvement (Table 1, entry 11), whereas the yield of
product decreased to 76%, when the amount of K2CO3 was
reduced to 1 equiv (Table 1, entry 16).
All the reactions were proceeded at room temperature.
Our studies commenced with a survey of solvents with
the goal of identifying efective conditions. When 4-chloro-
N-hydroxybenzenecarboximidoyl chloride (1 mmol) and
phenyl acetylene (1 mmol) were treated with 1 mol% of
Cu(II)/PBI, K2CO3 (2 mmol) in dichloromethane at room
temperature for 3 h, the expected reaction proceeded to give
the corresponding isoxazole in 18% yield (Table 1, entry 1).
Replacement of DMSO and acetone with CH2Cl2
(Table 1, entries 2, 3) did not give an improved outcome,
while the formation of corresponding product was mark-
edly improved when using the same reaction conditions
in THF, CH3CN, dioxane, PEG 300 and EtOH (Table 1,
entries 4–8).
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Journal of the Iranian Chemical Society
Improvement in the yield was not observed by increas-
ing the loading of the catalyst to 2 mol% (Table 1, entry
17), whereas decreasing the catalyst loading to 0.5 mol%
resulted in a lower yield of the product (Table 1, entry 18).
CuI, CuBr and CuCl can also be utilized in the cycload-
dition process. However, the use of these copper salts in
H2O resulted in lowered yields (Table 1, entries 19–21).
Without PBI, the yield of the reaction was decreased to
75% (Table 1, entry 22). Other attempt to carry out this
reaction without any catalyst was unsuccessful (Table 1,
entry 23).
(4), perhaps because of the relatively decreased water solu-
bility (Table 1, entry 4).
Next, diferent electron-withdrawing substituents on the
phenyl ring were tested with the catalytic system (Table 1,
entries 8–10).
When aldehyde bearing an ester group was employed,
the tandem reaction also successfully underwent (Table 2,
entry 8).
It should be emphasized that the isoxazole derivative con-
taining a thiophene ring was obtained in 92% yield under
similar reaction conditions (Table 2, entry 11).
We next explored the possibility of employing aliphatic
terminal alkynes as the substrate to react with imidoyl chlo-
ride under the standard conditions. The corresponding isoxa-
zoles were obtained in good to high yields (Table 2, entries
12–17).
After the extensive screening of reaction conditions, we
concluded that the most efcient set of conditions employs
1.0 equiv of imidoyl chloride, 1.0 equiv of alkyne, 2.0
equiv of K2CO3 and 1 mol% of Cu(II)/PBI in H2O at room
temperature.
On the basis of these screening results, to demonstrate
the scope of this reaction, a series of hydroximoyl chlorides
were reacted with various terminal alkynes at room tempera-
ture in the presence of 1 mol% of Cu(II)/PBI and K2CO3 as
the base for 3 h (Table 2). The results are summarized in
Table 2. As shown, almost all reactions proceeded to com-
pletion in 3 h and the corresponding products were obtained
in good to excellent yields.
Propargyl bromide and chloride were reacted under the
standard conditions. The corresponding products 12 and 13
were obtained in 89 and 88% yields, respectively.
Moreover, synthesized alkyl terminal alkynes from
4-methyl phenol and saccharin were also found to be suitable
reaction partners with the model compound in the reaction
(Table 2, entries 14–15).
In addition, propargylic alkynes could also react with
4-chlorobenzaldehyde to aford the corresponding prod-
ucts 16 and 17 in 75 and 80% yields, respectively (Table 2,
entries 16–17).
Substrates bearing electron-donating substituents on the
phenyl ring provided the corresponding products in high
yields (Table 2, entries 3–7).
However, introducing a bulky isopropyl group into the
parent aldehyde provided 85% yield of the desired isoxazole
Moreover, our catalytic system worked well under
gram-scale reaction conditions: reaction of 50 mmol of
Table 3 Comparison of protocols for the synthesis of isoxazole derivatives
Entry
Product
Time (h)
10
Yield (%)
54
Condition
Ref.
[40]
1
K2CO3, MeOH/H2O, 60 °C
2
3
Cu/CuSO4 , t-BuOH:H2O(1:1)
72
[14]
4
4
CuSO4.5H2O, 2 mol%, Sodium
ascorbate, 10 mol%, KHCO3,
H2O/t-BuOH, r.t
74
[41]
PdCl2(PPh3)2 (1 mol%), DMF-
H2O
4
5
6
7
54
85
76
95
[42]
[43]
[44]
37
CrO2, MeCN, 80 °C
Clay-Cu(II) (15 mol%), r.t
PBI / Cu(OAc)2(2 Mol%)
2
6
3
This
work
1 3

Journal of the Iranian Chemical Society
8. A.P. Kozikowski, S. Tapadar, D.N. Luchini, K.H. Kim, D.D. Bil-
ladeau, J. Med. Chem. 51, 4370 (2008)
4-chlorobenzaldehyde with phenyl acetylene gave the cor-
responding products 1 in 90% yield.
9. E.M. Pinho, M.V.D. Teresa, Curr. Org. Chem. 9, 925 (2005)
10. P.G. Baraldi, A. Barco, S. Benetti, G.P. Pollini, D. Simoni, Syn-
thesis 1987, 857–869 (1987)
The literature reports for the synthesis of 3,5-disubstituted
isoxazole derivatives in the presence of various catalysts are
listed in Table 3. The results demonstrate that the present
protocol is indeed superior to several of the other protocols.
The 3-(4-chlophenyl)-phenylisoxazole is produced in 3 h and
95% isolated yield using the present protocol. Most of the
other protocols listed take either longer time for completion
or use high temperature. Also, this protocol was employed to
give 3,5-diphenylisoxazole, 3-(4-nitrophenyl)-5-phenylisox-
azole and 3-(4-methoxyphenyl)-5-phenylisoxazole, in com-
parison with other procedure, in shorter reaction time with
excellent isolated yields. So, Cu(OAc)2 in the presence of
pyridinyl benzimidazole (PBI) as a bidentate N-chelating
ligand can be considered as an efcient catalyst in the syn-
thesis of 3,5-disubstituted isoxazole derivatives.
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In conclusion, we have reported a highly regioselective
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cycloaddition of alkynes with nitrile oxides. This catalytic
system provides an efcient method for the synthesis of
isoxazole derivatives.
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The synthetic value of the developed methodology was
demonstrated by the efcient preparation of a representa-
tive range of aldehydes and alkynes including gram-scale
synthesis of isoxazole derivatives.
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Acknowledgements We gratefully acknowledge the support of this
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30. S. Li, B. Zhang, F.E. Kühn, J. Organomet. Chem. 730, 132 (2013)
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