Synthesis of 3,4,5-substituted furan-2(5H)-ones using Al-doped ZnO nanostructure

Article abstract of DOI:10.1007/s11164-018-3406-0

Al-doped ZnO nanostructures were prepared via a simple precipitation method and were characterized by several techniques including XRD, TEM, EDX, UV–Vis, and DLS. All XRD patterns show the hexagonal single-phase structure of pure and Al-doped ZnO nanopowders without impurity. The samples consist of particles with average sizes ranging from 53 to 60?nm measured by DLS technique. Next, the catalytic activity of pure and Al-doped ZnO nanopowders was investigated in terms of synthesis of 3,4,5-substituted furan-2(5H)-one derivatives using the three-component reaction of aldehydes, aromatic amines, and acetylenic esters. This procedure has advantages such as high yields, simple methodology, and easy work-up.

Full text of DOI:10.1007/s11164-018-3406-0

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3406-0
Synthesis of 3,4,5-substituted furan-2(5H)-ones using
Al-doped ZnO nanostructure
Majid Ghashang1
Sadaf Janghorban1 Seyyed Jalal Roudbaraki2
•
•
Received: 24 November 2017 / Accepted: 19 March 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Al-doped ZnO nanostructures were prepared via a simple precipitation
method and were characterized by several techniques including XRD, TEM, EDX,
UV–Vis, and DLS. All XRD patterns show the hexagonal single-phase structure of
pure and Al-doped ZnO nanopowders without impurity. The samples consist of
particles with average sizes ranging from 53 to 60 nm measured by DLS technique.
Next, the catalytic activity of pure and Al-doped ZnO nanopowders was investi-
gated in terms of synthesis of 3,4,5-substituted furan-2(5H)-one derivatives using
the three-component reaction of aldehydes, aromatic amines, and acetylenic esters.
This procedure has advantages such as high yields, simple methodology, and easy
work-up.
Keywords 3,4,5-substituted furan-2(5H)-one Á Al-doped ZnO Á ZnO Á Acetylenic
esters Á Butenolides
Introduction
Furan-2(5H)-ones are a class of butenolides of major interest not only for their
presence in several biologically active compounds but also for their use as synthetic
intermediates [1–7]. In recent years, butenolide derivatives have been exploited
successfully as antimicrobial [8, 9], antifungal [10, 11], anti-inflammatory [12],
anticancer [13, 14] and anti-viral HIV-1 agents [15, 16]. Due to the high
&
Majid Ghashang
ghashangmajid@gmail.com
1
2
Department of Chemistry, Faculty of Sciences, Najafabad Branch, Islamic Azad University,
P.O. Box 517, Najafabad, Iran
Department of Chemistry, Faculty of Sciences, Lahijan Branch, Islamic Azad University,
Lahijan, Iran
123

M. Ghashang et al.
significance of substituted furan-2(5H)-ones in applications as effective drugs, it is
important to synthesize these compounds via a simple and efficient method. To date,
diverse synthetic methods have been reported including Passerini-like three-
component condensation [17], exo-selective cycloisomerization of acetylenic acids
[18], gold-catalyzed condensation reaction of alkynes, amines, and glyoxylic acid
[19], cross-coupling of allenyl carboxylic acids with vinyl/aryl halides catalyzed by
Pd–Ag [20], N-heterocyclic carbene catalyzed transformations [21], C–H activation
reaction of cyclo-alkenecarboxylic acids and acrylates [22], Morita–Baylis–Hillman
adducts [23], and three-component reaction of amines, aldehydes, and acetylenic
esters [24]. The latter method was designed for the synthesis of 3,4,5-substituted
furan-2(5H)-ones and was promoted by a few Lewis and Brønsted acids including
b-cyclodextrin [24], SnCl2 [25], ZnO nanoparticles [26, 27], Al(HSO4)3 [28], tetra-
n-butylammonium bisulfate [29], PPA/SiO2 [30], SnO nanoparticles [31], and HY
zeolite [32].
The widespread interest in the chemistry and therapeutic application of furan-
2(5H)-one derivatives stimulate us to continue our works on multi-component
reactions [33–44] and develop a new method for the preparation of 3,4,5-substituted
furan-2(5H)-ones using a novel nanostructure of Al-doped ZnO as a stable hetero-
geneous catalyst (Scheme 1).
Experimental
Reagents and instrumentation
Chemicals were purchased from Merck and Aldrich and used without further
purification. The catalyst characterizations were conducted on a HITACHI S-4160
field emission scanning electron microscope (FE-SEM) and a Bruker-AXS Advance
D8 X-ray diffractometer with Cu-Ka irradiation. The nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker Avance DPX 400 MHz instrument. The
spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). Elemental analysis
was performed on a Heraeus CHN-O-Rapid analyzer. Thin-layer chromatography
(TLC) was performed on silica gel Polygram SIL G/UV 254 plates.
Scheme 1 Preparation of 3,4,5-substituted furan-2(5H)-one derivatives
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
Preparation of nanostructured Al-doped ZnO
An aqueous ammonia solution (37%) was diluted by water (30 mL) and was drop-
wise added into a solution of mixed Al(NO3)3 (1 mmol) and Zn(NO3)2 (20 mmol)
in 50 mL of distilled water drop-wise under magnetic stirring. The obtained mixture
was stirred at room temperature for 30 min. The precipitate was filtered, washed
with distilled water, and dried. The precipitate was calcined at 500 °C in an electric
furnace for 2 h.
General procedure
Aldehyde (1 mmol), acetylenic esters (1 mmol), aromatic amine (1 mmol),
nanostructured Al-doped ZnO (0.025 g), and ethanol (5 mL) was charged into a
round-bottom flask. The resulting mixture was stirred at reflux condition for the
appropriate time (Table 4, monitored by TLC). Upon completion, the solvent was
concentrated and the reaction mixture was diluted in CHCl3; simple filtration
isolated the catalyst and the crude product was washed with diethyl ether to afford
the pure product.
Selected data:
Methyl
2-(benzofuran-2-yl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-car-
boxylate (18a): 1H-NMR (400 MHz, DMSO-d6): 3.75 (s, 3H, OCH3), 6.37 (s,
1H), 6.88 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.25–7.31 (m, 2H), 7.48–7.60 (m, 6H),
9.97 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 52.3, 69.6, 105.8, 112.0,
121.2, 121.9, 123.6, 124.8, 126.0, 126.8, 129.3, 129.4, 131.3, 140.8, 155.2, 157.1,
163.2, 166.1 ppm; found: C, 68.90; H, 4.49; N, 4.17 C20H15NO5; requires: C, 68.76;
H, 4.33; N, 4.01%.
Ethyl 2-(benzofuran-2-yl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxy-
1
late (19a): H-NMR (400 MHz, DMSO-d6): 1.27 (t, J = 6.8 Hz, 3H, CH3), 4.16
(q, J = 6.8 Hz, 2H, OCH2), 6.38 (s, 1H), 6.93 (s, 1H), 7.08 (t, J = 7.6 Hz, 1H),
7.25–7.31 (m, 2H), 7.47–7.61 (m, 6H), 10.02 (s, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): 14.2, 61.0, 69.8, 105.9, 111.9, 121.1, 121.8, 123.4, 124.8,
126.0, 126.8, 129.3, 129.4, 131.2, 140.8, 155.1, 157.0, 163.5, 166.3 ppm; found: C,
69.52; H, 4.87; N, 4.01 C21H17NO5; requires: C, 69.41; H, 4.72; N, 3.85%.
Methyl 2-(benzofuran-2-yl)-5-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-carboxy-
late (20a): 1H-NMR (400 MHz, DMSO-d6): 2.22 (s, 3H, CH3), 3.75 (s, 3H, OCH3),
6.36 (s, 1H), 6.89 (s, 1H), 7.07–7.17 (m, 4H), 7.26–7.32 (m, 2H), 7.52–7.56 (m,
2H), 10.04 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 21.5, 52.1, 70.0,
105.9, 111.9, 113.0, 121.8, 123.6, 125.8, 126.8, 129.3, 129.6, 131.2, 132.7, 141.0,
155.1, 157.1, 163.2, 166.1 ppm; found: C, 69.55; H, 4.89; N, 3.97 C21H17NO5;
requires: C, 69.41; H, 4.72; N, 3.85%.
Ethyl 2-(benzofuran-2-yl)-5-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-carboxy-
1
late (21a): H-NMR (400 MHz, DMSO-d6): 1.25 (t, J = 6.8 Hz, 3H, CH3), 2.23
(s, 3H, CH3), 4.16 (q, J = 6.8 Hz, 2H, OCH2), 6.34 (s, 1H), 6.91 (s, 1H), 7.09–7.16
(m, 4H), 7.27–7.31 (m, 2H), 7.52–7.56 (m, 2H), 10.08 (s, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): 14.2, 21.5, 60.8, 69.9, 106.0, 111.8, 113.0, 121.9, 123.4,
123

M. Ghashang et al.
125.8, 126.9, 129.4, 129.7, 131.3, 132.5, 140.8, 155.3, 157.2, 163.1, 166.2 ppm;
found: C, 70.21; H, 5.23; N, 3.80 C22H19NO5; requires: C, 70.02; H, 5.07; N, 3.71%.
Methyl 2-(benzofuran-2-yl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihydro-
1
furan-3-carboxylate (22a): H-NMR (400 MHz, DMSO-d6): 2.21 (s, 3H, CH3),
2.25 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.48 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H),
6.80–6.87 (m, 2H), 7.25–7.31 (m, 2H), 7.41 (s, 1H), 7.51–7.56 (m, 2H), 10.14 (s,
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 19.8, 20.7, 52.3, 73.2, 107.6,
112.1, 117.3, 120.8, 121.9, 124.1, 126.1, 127.0, 129.4, 130.3, 131.5, 132.4, 136.1,
141.1, 154.7, 157.2, 162.1, 165.1 ppm; found: C, 70.21; H, 5.24; N, 3.85
C22H19NO5; requires: C, 70.02; H, 5.07; N, 3.71%.
Ethyl 2-(benzofuran-2-yl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihydrofu-
ran-3-carboxylate (23a): 1H-NMR (400 MHz, DMSO-d6): 1.27 (t, J = 6.8 Hz,
3H, OCH2CH3), 2.20 (s, 3H, CH3), 2.24 (s, 3H, CH3), 4.16 (q, J = 6.8 Hz, 2H,
OCH2), 6.47 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.81–6.88 (m, 2H), 7.24–7.31 (m,
2H), 7.40 (s, 1H), 7.51–7.56 (m, 2H), 10.11 (s, 1H, NH) ppm; 13C-NMR (100 MHz,
DMSO-d6): 14.3, 19.9, 21.0, 61.2, 73.4, 107.8, 112.2, 117.5, 120.7, 121.8, 124.0,
126.2, 127.0, 129.3, 130.4, 131.6, 132.5, 136.0, 141.0, 154.6, 157.0, 162.2,
165.1 ppm; found: C, 70.86; H, 5.69; N, 3.77 C23H21NO5; requires: C, 70.58; H,
5.41; N, 3.58%.
Methyl 4-((3,4-dimethylphenyl)amino)-5-oxo-2-phenyl-2,5-dihydrofuran-3-car-
1
boxylate (24a): H-NMR (400 MHz, DMSO-d6): 2.21 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 3.74 (s, 3H, OCH3), 6.06 (s, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.89 (d,
J = 7.9 Hz, 1H), 7.31–7.39 (m, 4H), 7.45 (d, J = 7.8 Hz, 2H), 9.25 (s, 1H, NH)
ppm; 13C-NMR (100 MHz, DMSO-d6): 19.8, 21.1, 52.3, 86.6, 117.2, 121.1, 128.6,
128.9, 129.3, 129.7, 130.4, 131.4, 132.7, 135.1, 136.0, 141.2, 162.3, 164.9 ppm;
found: C, 71.45; H, 5.91; N, 4.31 C20H19NO4; requires: C, 71.20; H, 5.68; N, 4.15%.
Ethyl 4-((3,4-dimethylphenyl)amino)-5-oxo-2-phenyl-2,5-dihydrofuran-3-car-
1
boxylate (25a): H-NMR (400 MHz, DMSO-d6): 1.27 (t, J = 6.8 Hz, 3H, OCH2-
CH3), 2.21 (s, 3H, CH3), 2.25 (s, 3H, CH3), 4.15 (q, J = 6.8 Hz, 2H, OCH2), 6.07 (s,
1H), 6.68 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 7.29–7.40 (m, 6H), 9.08 (s,
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 14.4, 19.9, 21.1, 61.2, 86.7, 117.3,
121.2, 128.5, 128.9, 129.3, 129.6, 123.4, 131.4, 132.6, 135.0, 136.1, 141.1, 162.2,
165.1 ppm; found: C, 71.93; H, 6.22; N, 4.11 C21H21NO4; requires: C, 71.78; H,
6.02; N, 3.99%.
Methyl
4-((3,4-dimethylphenyl)amino)-5-oxo-2-(p-tolyl)-2,5-dihydrofuran-3-
1
carboxylate (26a): H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H, CH3), 2.24 (s,
3H, CH3), 2.28 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.25 (s, 1H), 6.69 (d, J = 8.0 Hz,
1H), 6.89 (d, J = 8.0 Hz, 1H), 7.14–7.20 (m, 4H), 7.41 (s, 1H), 8.98 (s, 1H, NH)
ppm; 13C-NMR (100 MHz, DMSO-d6): 19.8, 21.0, 21.6, 52.3, 86.8, 117.4, 121.2,
126.6, 129.3, 129.6, 130.2, 131.5, 132.7, 135.2, 136.3, 140.1, 141.1, 162.4,
165.1 ppm; found: C, 71.97; H, 6.23; N, 4.17 C21H21NO4; requires: C, 71.78; H,
6.02; N, 3.99%.
Ethyl 4-((3,4-dimethylphenyl)amino)-5-oxo-2-(p-tolyl)-2,5-dihydrofuran-3-car-
1
boxylate (27a): H-NMR (400 MHz, DMSO-d6): 1.26 (t, J = 6.8 Hz, 3H, OCH2-
CH3), 2.20 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.27 (s, 3H, CH3), 4.17 (q, J = 6.8 Hz,
2H, OCH2), 6.27 (s, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H),
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
7.14–7.21 (m, 4H), 7.41 (s, 1H), 9.03 (s, 1H, NH) ppm; 13C-NMR (100 MHz,
DMSO-d6): 14.5, 19.9, 21.2, 21.6, 61.1, 86.9, 117.4, 121.2, 126.7, 129.3, 129.7,
130.2, 131.5, 132.6, 135.4, 136.6, 140.2, 141.3, 162.4, 165.2 ppm; found: C, 72.55;
H, 6.59; N, 4.00 C22H23NO4; requires: C, 72.31; H, 6.34; N, 3.83%.
Methyl 2-(4-chlorophenyl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihydrofu-
1
ran-3-carboxylate (28a): H-NMR (400 MHz, DMSO-d6): 2.22 (s, 3H, CH3), 2.26
(s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.21 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.90 (d,
J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H),
9.34 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 19.9, 21.1, 52.4, 87.0,
117.4, 121.3, 127.8, 129.0, 129.5, 130.4, 131.3, 132.7, 135.2, 136.8, 136.9, 141.2,
162.4, 165.3 ppm; found: C, 64.84; H, 5.06; N, 3.91 C20H18ClNO4; requires: C,
64.61; H, 4.88; N, 3.77%.
Methyl 2-(3-chlorophenyl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihydrofu-
1
ran-3-carboxylate (29a): H-NMR (400 MHz, DMSO-d6): 2.21 (s, 3H, CH3), 2.25
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 6.17 (s, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.90 (d,
J = 7.8 Hz, 1H), 7.19–7.28 (m, 2H), 7.40–7.43 (m, 2H), 7.54 (s, 1H), 9.19 (s, 1H,
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 19.9, 21.2, 52.5, 86.9, 117.3, 121.4,
126.7, 127.7, 129.6, 129.9, 130.4, 130.6, 132.2, 132.7, 132.9, 136.7, 137.6, 141.2,
162.1, 165.2 ppm; found: C, 64.91; H, 5.12; N, 3.97 C20H18ClNO4; requires: C,
64.61; H, 4.88; N, 3.77%.
Methyl 2-(2-chlorophenyl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihydrofu-
1
ran-3-carboxylate (30a): H-NMR (400 MHz, DMSO-d6): 2.21 (s, 3H, CH3), 2.25
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 6.22 (s, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.89 (d,
J = 7.9 Hz, 1H), 7.26–7.31 (m, 2H), 7.39 (s, 1H), 7.53–7.59 (m, 2H), 9.07 (s, 1H,
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 19.8, 21.2, 52.3, 87.0, 117.4, 121.2,
127.6, 129.3, 129.8, 130.2, 130.5, 130.7, 131.7, 132.6, 133.0, 136.7, 137.3, 141.2,
162.3, 165.2 ppm; found: C, 64.89; H, 5.11; N, 3.93 C20H18ClNO4; requires: C,
64.61; H, 4.88; N, 3.77%.
Methyl 2-(4-(tert-butyl)phenyl)-4-((3,4-dimethylphenyl)amino)-5-oxo-2,5-dihy-
1
drofuran-3-carboxylate (31a): H-NMR (400 MHz, DMSO-d6): 1.27 (s, 9H), 2.20
(s, 3H, CH3), 2.24 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.27 (s, 1H), 6.69 (d,
J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.9 Hz, 2H), 7.23 (d,
J = 7.9 Hz, 2H), 7.39 (s, 1H), 8.87 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-
d6): 19.9, 21.1, 31.7, 34.9, 52.3, 86.8, 117.3, 121.2, 125.4, 126.8, 129.4, 130.2,
131.4, 132.7, 134.8, 136.3, 141.1, 153.7, 162.3, 165.1 ppm; found: C, 73.43; H,
7.11; N, 3.74 C24H27NO4; requires: C, 73.26; H, 6.92; N, 3.56%.
Methyl 4-((3,4-dimethylphenyl)amino)-2-(4-methoxyphenyl)-5-oxo-2,5-dihydro-
furan-3-carboxylate (32a): 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H, CH3), 2.24
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.39 (s, 1H), 6.69 (d,
J = 7.9 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 7.38–7.41 (m,
3H), 8.56 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): 19.9, 21.2, 52.3,
55.7, 86.9, 114.4, 117.3, 121.1, 125.3, 129.4, 130.2, 131.5, 132.6, 135.2, 136.4,
141.2, 160.3, 162.4, 165.3 ppm; found: C, 68.86; H, 5.99; N, 4.02 C21H21NO5;
requires: C, 68.65; H, 5.76; N, 3.81%.
Methyl 4-((3,4-dimethylphenyl)amino)-2-(3-methoxyphenyl)-5-oxo-2,5-dihydro-
furan-3-carboxylate (33a): 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H, CH3), 2.24
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M. Ghashang et al.
(s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 6.19 (s, 1H), 6.69 (d,
J = 7.8 Hz, 1H), 6.88–6.91 (m, 2H), 7.06 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.29 (t,
J = 7.9 Hz, 1H), 7.39 (s, 1H), 8.74 (s, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-
d6): 19.8, 21.0, 52.4, 55.7, 86.8, 111.2, 115.2, 117.3, 121.1, 126.5, 129.4, 130.2,
130.5, 131.7, 132.6, 136.4, 137.7, 141.0, 159.5, 162.4, 165.0 ppm; found: C, 68.84;
H, 5.96; N, 3.98 C21H21NO5; requires: C, 68.65; H, 5.76; N, 3.81%.
Methyl
4-((3,4-dimethylphenyl)amino)-5-oxo-2-(o-tolyl)-2,5-dihydrofuran-3-
1
carboxylate (34a): H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H, CH3), 2.24 (s,
3H, CH3), 2.25 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 6.21 (s, 1H), 6.69 (d, J = 7.9 Hz,
1H), 6.88–6.95 (m, 2H), 7.06–7.19 (m, 4H), 7.39 (s, 1H), 8.64 (s, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): 19.9, 21.1, 19.7, 52.3, 86.7, 117.3, 121.0, 126.5,
128.5, 129.4, 129.9, 130.2, 130.7, 131.6, 132.7, 135.6, 136.1, 137.2, 141.1, 162.3,
165.1 ppm; found: C, 71.94; H, 6.29; N, 4.26 C21H21NO4; requires: C, 71.78; H,
6.02; N, 3.99%.
Result and discussion
Catalyst characterization
To obtain information about the phase characteristics of the synthesized materials,
X-ray diffraction (XRD) analysis was performed. Figure 1 shows the XRD patterns
of pure and Al-doped ZnO nanopowders calcined at 500 °C for 2 h. The hexagonal
single-phase structure (space group P63mc) was observed in the XRD pattern of the
powders which is in agreement with the reported standard values (JCPDS 01-079-
Fig. 1 XRD pattern of pure and Al-doped ZnO nanostructure
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
2205) [45]. The characteristic peaks of hexagonal ZnO are 31.76, 34.42, 36.25,
47.52, 56.56, 62.81, 66.40, 67.88, 69.03, and 76.90 [2h°]. The XRD patterns do not
show impurity peaks related to Al phases which indicates that Al ions were entirely
substituted by Zn sites in the lattices of ZnO crystal. Also, the highest peak (36.25
2h°) for pure ZnO led to a positive change in the broadening and location which
agrees with decreasing the grain size (Fig. 2). The crystalline size, microstrain (e),
and dislocation density of the samples were determined from the full width at half
maximum (FWHM) of the highest peak of the XRD pattern (Table 1). The crystal
sizes of the samples are 61, 50, and 56 nm for pure ZnO, 2% Al, and 5% Al,
respectively. A smaller crystal size was observed for the sample containing 2% Al,
and after that, it decreased with the increase of Al concentration. In general, because
of smaller crystal size, the microstrain and dislocation density of Al-doped ZnO
samples are bigger than those of pure ZnO [45].
Transmission electron microscopy (TEM) analysis was used to determine the
morphological structure of the nanostructured ZnO and Al-doped ZnO (Fig. 3). The
particles are homogeneous and nearly uniformly spherical with dimensions less than
100 nm. The results show that the shape of the doped particles does not change
obviously compared with pure ZnO. The chemical composition of pure ZnO and Al-
doped ZnO nanostructures were determined by energy-dispersive X-ray spec-
troscopy (EDX) analysis (Fig. 4). The results of EDX analysis confirm the chemical
constituents of three samples (0, 0.69, and 1.69% of Al element). The dynamic
light-scattering (DLS) technique was used to determine the particle size distribution
of the pure ZnO and Al-doped ZnO nanostructure samples. Before analysis, 1 g of
each sample was dispersed in 20 mL of ethanol by ultrasonic irradiation for 30 min.
According to DLS measurement, the nanoparticles have an average size of 60 (pure
ZnO), 56 (2% Al), and 53 nm (5% Al; Fig. 5).
The UV absorption spectra of pure ZnO and Al-doped ZnO nanostructures
samples show strong absorption peaks at 360, 356, and 349 nm for pure ZnO, 2%
Fig. 2 Changes in the broadening and location of the highest peak (36.25 2h°)
123

M. Ghashang et al.
Table 1 Data of high-intensity XRD peaks for pure and Al-doped ZnO nanostructures
Sample Crystal system Peak
(space group)
FWHM Average crystallite
b (2h°)
Microstrain Dislocation
b cos h
density (d)
(e) e ¼
position
(2h°)
size A (nm)
0:9k
4
1
d ¼
A2
A ¼
b cos h
Pure
ZnO
Hexagonal
(P63mc)
36.2516
36.4019
36.557
0.2357
0.2863
0.2569
61.874
50.917
56.818
0.056
0.068
0.061
2.612 9 10-4
3.857 9 10-4
3.098 9 10-4
2% Al Hexagonal
(P63mc)
5% Al Hexagonal
(P63mc)
Al, and 5% Al samples, respectively (Fig. 6). From the theory of the Moss–Burstein
effect, there is a blue shift with simultaneous peak broadening in the peaks related to
Al-doped ZnO samples compared with pure ZnO [39]. The samples’ band gaps were
calculated as 3.45 (pure ZnO), 3.49 (2% Al), and 3.56 (5% Al) from the following
equation:
1241
EðevÞ ¼
kðnmÞ
where k(nm) is the absorption peaks of the samples.
The increase in the band gap of the samples from pure ZnO to 5% Al impurity is
due to the quantum size effect which causes a blue shift in the absorption [46].
Brunauer–Emmet–Teller (BET) surface area technique was used to determine the
specific surface area of the samples as 30.14 m2 g-1 (2% Al), 29.64 m2 g-1 (5%
Al), and 9.97 m2 g-1 for pure ZnO.
Investigation of the catalytic activity
At first, the catalytic activities for the synthesis of 4 through the transformation of 1,
2, and 3 using some of the metal oxides were measured to elucidate the effect of
metal oxides (Scheme 2, Table 2). The order of metal oxides on the 4 formation rate
is Al-doped ZnO (2% Al) [ Al-doped ZnO (5% Al) [ ZnO [ MgO [ SnO2. Some
catalysts, including Al2O3, SiO2, Fe2O3, and CaO, were found to be non-effective in
the reaction. In this study, Al-doped ZnO was found to be a more effective catalyst
for 4 (85% yield) synthesis than ZnO (80% yield) which is a suitable metal oxide for
the above transformation. Doping of Al promoted the catalytic activity of ZnO
(Table 2).
The results of performed experiments showed that the solvent has an anomalous
effect on the productivity of the reaction (Table 3). Unlike polar solvents which
have to result in moderate to good yields, use of non-polar solvents and also solvent-
free condition is not effective. Consequently, per the obtained results, EtOH is the
more suitable solvent for the reaction medium. Next, the effect of catalyst dosage
(varying from 0.1 to 1 mmol) on the product yield was investigated. An excellent
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
Fig. 3 TEM images of pure ZnO and Al-doped ZnO nanostructures
yield of product was obtained when 0.3 mmol of catalyst was used. The further
increase in the catalyst dosage did not show any significant increase in the product
yield (Table 3).
A plausible proposed mechanism for the formation of 3,4,5-substituted furan-
2(5H)-ones is shown in Scheme 3. At first, the nucleophilic attack of an aromatic
amine to dialkyl acetylenedicarboxylate results in the generation of intermediate
123

M. Ghashang et al.
Fig. 4 Chemical composition of pure ZnO and Al-doped ZnO nanostructures using EDX analysis
a. At the same time, aromatic aldehyde was activated by Al-doped ZnO as a catalyst
to form an activated carbonyl group (b). Subsequently, the reaction of intermediate
a with activated aromatic aldehyde to form intermediate c which is equilibrated with
intermediate d. The cyclization reaction produced 3,4,5-substituted furan-2(5H)-
ones.
Although the rule of Al-doped ZnO in catalytic processes is the same with those
of pure ZnO, the product yields for doped samples are higher which may be due to
the higher surface area of doped samples (30.14 and 29.64 m2 g-1) compared with
pure ZnO (9.97 m2 g-1).
Next, using the optimized conditions (Table 3: catalyst (0.3 mmol), ethanol,
reflux), diverse anilines, aldehydes, and acetylenic esters reacted together to give the
corresponding 3,4,5-substituted furan-2(5H)-ones (Scheme 1, Table 4). It was
found that the yields and product purity for all products including electron-donating
and electron-withdrawing groups (EDGs and EWGs, respectively) substituted on
the aromatic rings are good (Table 4, products 1a–34a). Aromatic aldehydes and
amines bearing EWGs require more time to complete the reaction, whereas this time
is less for the donor substitutions. The substitution groups in the ortho position will
increase reaction time.
In contrast with the substitution of the EDG such as methyl (3a, 4a) or tert-butyl
(6a, 7a), aldehydes bearing EWGs such as chlorine (5a) showed diminished
activity. The activity of aromatic aldehydes can be increased when they are
coordinated to the ZnO catalyst. The capability of the carbonyl coordination of
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
Fig. 5 Particle size distribution analysis of pure ZnO and Al-doped ZnO nanostructures using DLS
technique
Fig. 6 UV absorption analysis of pure ZnO and Al-doped ZnO nanostructures
123

M. Ghashang et al.
Scheme 2 Preparation of methyl 4-(p-tolylamino)-2,5-dihydro-5-oxo-2-phenylfuran-3-carboxylate
Table 2 Catalyst screening
Entry
Catalyst (0.6 mmol)
Yield (%)a
1
2
3
4
5
6
7
8
9
SnO2
30
–
Al2O3
SiO2
–
Fe2O3
–
MgO
65
–
CaO
ZnO
80
85
84
aIsolated yields; reaction
condition: solvent: EtOH, reflux,
time: 8 h
Al-doped ZnO (2% Al)
Al-doped ZnO (5% Al)
Table 3 Optimization of the reaction condition in the synthesis of methyl 2,5-dihydro-5-oxo-2-phenyl-
4-(phenylamino)furan-3-carboxylate
Entry
Catalyst (mmol)
T (°C)
Solvent (5 mL)
Time (h)
Yield (%)a
1
0.6
0.6
0.6
0.6
0.6
0.6
0.6
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
n-Hexane
CH2Cl2
Et2O
10
10
10
10
8
–
2
–
3
–
4
EtOAc
EtOH
15
85
79
–
5
6
MeOH
Solvent-free
EtOH
8
7
10
10
8
8
r.t.
–
9
0.3
0.8
1
Reflux
Reflux
Reflux
EtOH
87
86
84
10
11
EtOH
8
EtOH
8
r.t. Room temperature
aIsolated yields
aromatic aldehydes strongly dependent on the electronic nature of the aldehyde.
Electron-rich aldehydes are more efficient substrates than those bearing electron-
withdrawing substituents. The reaction of p-methylbenzaldehyde was completed in
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
H
CO2R
ArNH2 +
RO2C
RO2C
CO2R
HN
a
Ar
ZnO
O
Ar-CHO + ZnO
b
Ar
Ar
H
ZnO
O
Ar
ZnO
O
-H+
RO2C
H
a + b
CO2R
RO2C
N
CO2R
d
Ar
N
c
H
Ar
Cyclization
-ROH
Ar
-ZnO
HN
RO2C
Ar
O
O
Scheme 3 Proposed mechanism for the formation of 3,4,5-substituted furan-2(5H)-ones
shorter reaction time and is higher-yielding than 4-chlorobenzaldehyde (Table 4,
entries 1a–7a).
On the other hand, during the reaction course, the nucleophilic Michael addition
of the aromatic amines to the dialkyl acetylenedicarboxylate generates the
aminobutendioate as an electron-rich enaminone and an active nucleophile.
Aromatic amines that are substituted by EDGs such as 4-methyl or 3,4-dimethyl
(Table 4) are more reactive intermediates than those of EWGs such as chlorine
(Table 4, entries 8a–9a).
The other factor that influences the reaction rate is steric hindrance.
2-Chlorobenzaldehyde afforded the product in lower yield in longer reaction time,
probably because of steric hindrance (Table 4, entries 15a, 16a, 17a).
Noticeably, we found that the above reactions could lead to the desired products
under ultrasonic irradiation condition in high yields and shorter reaction times; the
results are summarized in Table 4.
1
The H-NMR spectrum (in DMSO-d6) of compound 22a as a model showed a
singlet related to the Ha (furanone sp3 proton) at d = 6.48 ppm. A singlet appearing
at d = 10.14 was assigned to an N–H proton. The aromatic protons from the ortho
position of the amine moiety appear as a doublet at 6.69 ppm and a singlet at around
6.80–6.87 which is overlapped with the only meta proton of the amine ring. The
123

M. Ghashang et al.
Table 4 Synthesis of 3,4,5-substituted furan-2(5H)-one derivatives (Scheme 1)
Product Aldehyde
Amine
R
A
Time
B
Time
(h)/yield (%)a (h)/yield (%)a
1a
Benzaldehyde
4-Methylaniline
4-Methylaniline
4-Methylaniline
4-Methylaniline
4-Methylaniline
4-Methylaniline
4-Methylaniline
4-Chloroaniline
4-Chloroaniline
4-Methoxyaniline
Aniline
Me 8/87
Et 8/89
Me 7/93
Et 7/88
4/90
4/85
4/95
4/86
4/93
4/90
4/86
5/87
5/89
3/91
4/84
5/90
4/85
5/80
7/92
8/83
8/86
6/92
7/91
6/90
7/96
6/94
7/80
4/86
4/89
4/93
4/90
6/87
6/89
7/91
4/85
4/87
4/87
6/89
2a
Benzaldehyde
3a
4-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
4-tert-Butylbenzaldehyde
4-tert-Butylbenzaldehyde
4-Methylbenzaldehyde
Benzaldehyde
4a
5a
Me 8/89
Me 7/93
6a
7a
Et
7/87
8a
Me 9/86
Me 10/85
Me 6/96
Me 8/87
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
29a
30a
31a
32a
33a
34a
4-Methylbenzaldehyde
Benzaldehyde
Benzaldehyde
Aniline
Et
Me 8/86
Et 9/87
10/85
4-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
2-Chlorobenzaldehyde
2,4-Dichlorobenzaldehyde
Aniline
Aniline
Aniline
Me 11/86
Me 12/81
Me 15/80
Me 10/93
Aniline
Aniline
Benzofuran-2-carbaldehyde Aniline
Benzofuran-2-carbaldehyde Aniline
Et
Me 10/94
Et 11/86
12/90
Benzofuran-2-carbaldehyde 4-Methylaniline
Benzofuran-2-carbaldehyde 4-Methylaniline
Benzofuran-2-carbaldehyde 3,4-Dimethylaniline Me 10/88
Benzofuran-2-carbaldehyde 3,4-Dimethylaniline Et 11/89
3,4-Dimethylaniline Me 8/93
3,4-Dimethylaniline Et 9/86
3,4-Dimethylaniline Me 8/97
3,4-Dimethylaniline Et 8/92
Benzaldehyde
Benzaldehyde
4-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
3-Chlorobenzaldehyde
2-Chlorobenzaldehyde
4-tert-Butylbenzaldehyde
4-Methoxybenzaldehyde
3-Methoxybenzaldehyde
2-Methylbenzaldehyde
3,4-Dimethylaniline Me 10/86
3,4-Dimethylaniline Me 10/84
3,4-Dimethylaniline Me 12/96
3,4-Dimethylaniline Me 8/89
3,4-Dimethylaniline Me 8/89
3,4-Dimethylaniline Me 8/90
3,4-Dimethylaniline Me 10/84
aIsolated yields. A: EtOH, reflux; B: EtOH, 70 °C, ultrasonic irradiation. Products 1a–17a are reported
previously [24–32], and products 18a–34a are new and were characterized by their NMR and CHN
analysis
123

Synthesis of 3,4,5-substituted furan-2(5H)-ones using…
Scheme 4 Structure of methyl
4-(3,4-dimethylphenylamino)-2-
(benzofuran-2-yl)-2,5-dihydro-
5-oxofuran-3-carboxylate
(compound 22a)
O
CH3
CH3
H
N
O
Ha
Hb
O
O
O
proton assigned as Hb (Scheme 4) appears at d = 7.41 as a singlet. Two multiplets
appearing at around 7.25–7.31 and 7.51–7.56 ppm are related to aromatic protons of
the benzofuran moiety. Finally, three singlets appearing at 2.21, 2.25, and 3.75
integrated for para methyl, meta methyl, and methoxy protons, respectively.
The 13C-NMR spectrum of compound 22a showed 22 distinct resonances. Some
of them are assigned as 19.8 (CH3), 20.7 (CH3), 52.3 (OCH3), 73.2 (C-sp3 benzylic
furanone ring), 162.1 (–COOCH3), and 165.1 (COO furanone ring) ppm.
Significantly, after completion of the reaction, the catalyst could be successfully
recovered from the crude reaction mixture and reused for further catalytic cycles.
The results of catalyst recovery showed that the catalyst could be recycled five times
without apparent decrease in the catalytic efficiency (Fig. 7). Moreover, our
investigation revealed that the catalyst is stable in the reaction conditions and its
structure does not change after recovery. The XRD patterns of fresh and reused
catalyst are shown in Fig. 8 and confirm the stability of the catalyst.
Fig. 7 Reusability of Al-doped ZnO nanostructure (2% Al) as a catalyst
123

M. Ghashang et al.
Fig. 8 The XRD patterns of fresh and reused Al-doped ZnO nanostructure (2% Al) as a catalyst
Conclusion
In summary, nanostructured Al-doped ZnO was prepared via a simple precipitation
method and was applied as a mild and efficient green catalyst for the syntheses of
3,4,5-substituted furan-2(5H)-one derivatives. Various substituted amines and
aldehydes were used in the reaction. All products were obtained in good to
excellent yields. From the standpoint of the reaction conditions, it can be said that
the advantages of this method are mild conditions and high yields.
Acknowledgements We are thankful to the Najafabad Branch of the Islamic Azad University Research
Council for partial support of this research.
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