CuI-catalyzed, one-pot synthesis of 3-aminobenzofurans in deep eutectic solvents

Article abstract of DOI:10.1002/aoc.6433

An environmentally friendly method is presented here for the synthesis of various benzofuran derivatives using CuI catalyst. In this line, a one-pot, 3-component reaction of alkynes, different aldehydes, and amines is employed in choline chloride-ethylene

Full text of DOI:10.1002/aoc.6433

Received: 15 July 2021
DOI: 10.1002/aoc.6433
Revised: 10 August 2021
Accepted: 19 August 2021
R E S E A R C H A R T I C L E
CuI-catalyzed, one-pot synthesis of 3-aminobenzofurans in
deep eutectic solvents
Bahareh Abtahi | Hossein Tavakol
Department of Chemistry, Isfahan
An environmentally friendly method is presented here for the synthesis of vari-
ous benzofuran derivatives using CuI catalyst. In this line, a one-pot,
3-component reaction of alkynes, different aldehydes, and amines is employed
in choline chloride-ethylene glycol deep eutectic solvent as an available, cheap,
and green media. The employed method includes easy workup and good
yields. In this work, 12 different benzofuran derivatives have been prepared in
7 h at 80ꢀC.
University of Technology, Isfahan, Iran
Correspondence
Hossein Tavakol, Department of
Chemistry, Isfahan University of
Technology, Isfahan 84156-83111, Iran.
Email: h_tavakol@iut.ac.ir
Funding information
Isfahan University of technology
K E Y W O R D S
benzofuran, catalyst, choline chloride-ethylene glycol deep eutectic, cyclization, green
1 | INTRODUCTION
(known as A3-coupling) is considered in the present
work, which normally produces propargyl amines (as we
Benzofuran skeletons[1] are important heterocyclic com-
pounds because of their biological applications such
as antioxidative,[2] anticancer,[3] anti-inflammatory,[4]
mutagenic,[5] adenosine antagonist XH-14 inhibition,[6]
and 5-lipoxygenase inhibition.[7] These compounds have
been found as the important building blocks in synthetic
and natural bioactive products.[8] Therefore, several syn-
thetic methods have been developed for these compounds
to provide different ways for the global demands. Some of
these methods are decarboxylation,[9] cyclization of some
ketone derivatives,[10] reaction of 2-chlorophenols
with terminal alkynes,[11] the sigmatropic reactions of
aromatics,[12] coupling of N-tosylhydrazones and terminal
alkynes,[13] and the other methods.[14] In the most of
developed methodologies, some issues such as long reac-
tion time, nongenerality, multisteps production (including
separation of intermediates), hard condition, and using
hazardous reagents have been limited the application of
these strategies. Therefore, it is important to present more
appropriate methodologies to prepare various benzofurans
using available chemicals and easier procedure.
reported recently). Using mild and environmentally
friendly conditions, avoiding toxic reagents, no moisture
sensitivity, and high atom economy are the advantages of
the one-pot A3-coupling.[15–18] However, in some reports,
this reaction was used for the synthesis of different ben-
zofurans.[19] It is predictable that by using ortho-
hydroxybenzaldehyde derivatives (instead of simple benz-
aldehyde without ortho-hydroxy group) in this reaction,
after the preparation of aromatic propargyl amines, an
intermolecular nucleophilic attack of the ortho-hydroxy
group to the Cu-activated triple bond could lead to the
ring closure and produce the fused rings. Several
researches reported using both homogeneous and hetero-
geneous catalysts in this method.[20] Transition metal cat-
alytic systems like copper[21,22] and silver[23] salts have
been employed in this reaction for both C–H activation
(for nucleophilic attack to the iminium salt) and ring clo-
sure steps. According to the recent publications, copper
salts are better than other choices, and they are available
and cheap in addition to their low toxicity and high reac-
tivity.[24] Because of some disadvantages of this reaction
that have been reported in many studies, such as using
toxic solvents and employing expensive catalysts, it is
The transition metal-catalyzed reaction of secondary
amines, different aldehydes, and terminal alkynes
Appl Organomet Chem. 2021;e6433.
wileyonlinelibrary.com/journal/aoc
© 2021 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6433

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ABTAHI AND TAVAKOL
necessary to find a more appropriate and environmen-
tally friendly synthetic method to prepare benzofurans
using A3-coupling reaction. In order to decrease environ-
mental pollutions, a green and biodegradable media must
be employed to obey principles of the green chemistry.[25]
Therefore, volatile and toxic solvents were replaced with
ionic liquids (ILs) to decrease the environmental hazards
of these techniques. Despite the desirable specifications
of common ILs including low flammability, small vapor
pressure, thermal stability, and recyclability, using these
media was limited by some issues such as high-cost and
complex synthetic procedure.[26,27] Instead, their new
generation, named as deep eutectic solvents (DESs),[28]
solved the most of these problems, in addition to covering
the common benefits of ILs.[29] Following the previous
works of this group to develop the synthetic methodolo-
gies by using DESs[30–33] and a recent report on prepara-
tion of benzofuran derivatives,[34] the preparation of
benzofuran derivatives has been considered under green
media condition in this study.
were used freshly or up to 1 month after their
preparations.
2.2 | The synthesis of benzofurans
Choline chloride (0.14 g, 1 mmol), ethylene glycol
(0.12 g, 2 mmol), and CuI (0.01 g, 0.05 mmol) were
poured into a flask, on a magnetic heater–stirrer, and
heated to 80ꢀC and remained at this temperature for 1 h.
Next, 1 mmol of salicylaldehyde, 1.2 mmol of alkyne, and
1.5 mmol of amine were added. The mixture was
remained for 7 h at that temperature (Scheme 1). The
reaction has been monitored using thin layer chromatog-
raphy (TLC) (4:1 mixture of n-hexane:EtOAc as eluent),
then lets it to reach to r.t., and 10-mL EtOAc and 10-mL
H2O were added. After this, the organic layer, consisted
of the product, was separated from the other phases and
dried using MgSO4. After evaporating the solvent, the
product was purified using 20 Â 20 cm2 silica gel TLC.
The structures of the reported products were confirmed
by comparing their spectral data and physical properties
with the recorded data. For new derivatives, in addition
to the full spectral analysis, elemental analysis was
employed to confirm their structures. All spectral data
are listed in the next section. Moreover, all the original
spectra are reported in Supporting Information.
2 | EXPERIMENTAL
All compounds were purchased from Merck and Sigma-
Aldrich companies and they were purified if necessary.
The
starting
materials
were
purified
when
necessary. Infared (IR) spectroscopy analyses have been
performed using KBr disks and employing JASCO FT-IR
spectrophotometers in 400–4000 cmÀ1 region. 1H-NMR
(400 MHz, CDCl3) and 13C-NMR (100 MHz, CDCl3) spec-
tra have been obtained using Bruker Ultra shield
instrument.
2.3 | Physical and spectral data
2.3.1 | 4a: 4-(2-Benzyl-5-bromobenzofuran-
3-yl)morpholine
Yellow oil; IR (KBr, cmÀ1): 3063, 3026, 2971, 2891, 2853,
2752, 2681, 1949, 1803, 1727, 1601, 1448, 1378, 1267,
1201, 1113, 1033, 888, 805, 708; 1H-NMR (400 MHz,
CDCl3): δ = 3.06 (m, 4H, CH2-N), 3.77 (m, 4H, CH2-O),
4.08 (s, 2H, CH2 aliphatic), 7.19 (m, 7H, CH aromatic), 7.71
(d, J = 1.8 Hz, 1H, CH aromatic) ppm; 13C-NMR (100 MHz,
CDCl3): δ = 32.36 (CH2 aliphatic), 52.49 (CH2-N), 67.63
(CH2-O), 113.14, 115.24, 122.47, 126.36, 126.66, 128.05,
128.28, 128.53, 128.66, 137.74, 151.73, 152.21 (all for aro-
matic rings) ppm.
2.1 | Preparation of various DESs
All DESs (simply or mixed with metal salts) have been
prepared by simple mixing of ChCl, urea, or ethylene gly-
col and other components (such as CuCl2.2H2O,
FeCl3.6H2O, SnCl2.2H2O, ZnCl2.2H2O, NiCl2.6H2O), as
the previous reports.[35–38] For each DES, an appropriate
temperature and sufficient mixing time were employed,
based on the used ingredients. The prepared DESs
SCHEME 1 General reaction for
synthesis of benzofuran derivatives

ABTAHI AND TAVAKOL
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2.3.2 | 4b: 4-(2-Benzyl-5-chlorobenzofuran-
3-yl)morpholine
2.3.5 | 4e: 4-(2-(4-(Tert-butyl)benzyl)-
5-chlorobenzofuran-3-yl)morpholine
Yellow oil; IR (KBr, cmÀ1): 3090, 3022, 2918, 2855,
2824, 2752, 2677, 1949, 1865, 1729, 1603, 1449, 1376,
1258, 1206, 1172, 1109, 1064, 806, 712; 1H-NMR
(400 MHz, CDCl3): δ = 3.16 (m, 4H, CH2-N), 3.87
(m, 4H, CH2-O), 4.18 (s, 2H, CH2 aliphatic), 7.19
(dd, J1 = 8.6 Hz, J2 = 2.1 Hz, 1H, CH aromatic), 7.30
(m, 6H, CH aromatic), 7.66 (d, J = 2.0 Hz, 1H,
Yellow oil; IR (KBr, cmÀ1): 3086, 2960, 2909, 2852, 2752,
2681, 1906, 1805, 1738, 1608, 1512, 1451, 1370, 1263, 1114,
1041, 915, 806, 738, 538; 1H-NMR (400 MHz, CDCl3):
δ = 1.34 (s, 9H, CH3 aliphatic), 3.18 (m, 4H, CH2-N), 3.88
(m, 4H, CH2-O), 4.16 (s, 2H, CH2 aliphatic), 7.22 (m, 3H,
CH aromatic), 7.35 (m, 3H, CH aromatic), 7.66 (d, J = 2.6 Hz,
1H, CH aromatic) ppm; 13C-NMR (100 MHz, CDCl3):
δ = 31.29 (CH3 aliphatic), 31.86 (CH2 aliphatic), 34.48
(C aliphatic), 52.68 (CH2-N), 67.65 (CH2-O), 112.62, 119.43,
123.59, 125.57, 127.47, 127.67, 128.19, 128.35, 134.65,
149.52, 151.85, 152.11 (all for aromatic rings) ppm. Ele-
mental anal. for C23H26ClNO2 (C, 71.96; H, 6.83; Cl,
9.23; N, 3.65; O, 8.33); Found: C, 70.77; H, 5.76; N, 3.19.
CH
)
ppm; 13C-NMR (100 MHz, CDCl3):
aromatic
δ = 32.43 (CH2 aliphatic), 52.50 (CH2-N), 67.64 (CH2-O),
112.64, 119.47, 123.67, 126.65, 127.44, 127.74, 128.44,
128.55, 128.65, 128.83, 130.90, 137.77, 151.89 (all for
aromatic rings) ppm.
2.3.3 | 4c: 4-(2-Benzylbenzofuran-3-yl)
morpholine
2.3.6 | 4f: 4-(2-(4-(Tert-butyl)benzyl)
benzofuran-3-yl)morpholine
Yellow oil; IR (KBr, cmÀ1): 3055, 3024, 2961, 2851, 2815,
2749, 2678, 1940, 1709, 1602, 1495, 1450, 1380, 1257,
Yellow oil; IR (KBr, cmÀ1): 3054, 2959, 2901, 2856, 2749,
2681, 1903, 1800, 1730, 1611, 1512, 1453, 1382, 1261,
1207, 1113, 1022, 914, 833, 746; 1H-NMR (400 MHz,
CDCl3): δ = 1.33 (s, 9H, CH3 aliphatic), 3.22 (m, 4H, CH2-
N), 3.89 (m, 4H, CH2-O), 4.17 (s, 2H, CH2 aliphatic), 7.23
(m, 3H, CH aromatic), 7.35 (m, 3H, CH aromatic), 7.41 (d,
J = 9.0 Hz, 1H, CH aromatic), 7.70 (d, J = 8.7 Hz, 1H, CH
aromatic) ppm; 13C-NMR (100 MHz, CDCl3): δ = 31.39
(CH3 aliphatic), 31.88 (CH2 aliphatic), 34.36 (C aliphatic), 52.64
(CH2-N), 67.74 (CH2-O), 111.71, 119.89, 122.06, 123.42,
125.49, 126.14, 128.21, 135.08, 149.34, 150.47, 153.50 (all
for aromatic rings) ppm.
1
1210, 1111, 1033, 902, 748; H-NMR (400 MHz, CDCl3):
δ = 3.20 (m, 4H, CH2-N), 3.87 (m, 4H, CH2-O), 4.19 (s,
2H, CH2 aliphatic), 7.23 (m, 3H, CH aromatic), 7.32 (m, 3H,
CH aromatic), 7.40 (d, J = 7.40 Hz, 1H, CH aromatic), 7.69
(d, J = 7.0 Hz, 1H, CH aromatic) ppm; 13C NMR (100 MHz,
CDCl3): δ = 32.31 (CH2 aliphatic), 52.57 (CH2-N), 67.73
(CH2-O), 111.71, 119.91, 122.10, 123.48, 126.11, 126.48,
128.56, 128.77, 138.20, 140.75, 150.25, 153.52 (all for aro-
matic rings) ppm.
2.3.4 | 4d: 4-(5-Bromo-2-(4-(tert-butyl)
benzyl)benzofuran-3-yl)morpholine
2.3.7 | 4g: 4-(2-Benzyl-
7-methoxybenzofuran-3-yl)morpholine
Yellow oil; IR (KBr, cmÀ1): 3061, 2959, 2926, 2855, 2755,
1903, 1805, 1735, 1607, 1512, 1449, 1366, 1264, 1208,
1114, 1021, 804, 542; 1H-NMR (400 MHz, CDCl3):
δ = 1.34 (s, 9H, CH3 aliphatic), 3.18 (m, 4H, CH2-N), 3.88
(m, 4H, CH2-O), 4.16 (s, 2H, CH2 aliphatic), 7.26 (m, 4H,
CH aromatic), 7.36 (d, J = 11.0 Hz, 1H, CH aromatic), 7.82
(d, J = 2.1 Hz, 1H, CH aromatic) ppm; 13C-NMR (100 MHz,
CDCl3): δ = 31.38 (CH3 aliphatic), 31.85 (CH2 aliphatic),
34.45 (C aliphatic), 52.54 (CH2-N), 67.65 (CH2-O), 113.13,
115.21, 122.44, 125.57, 126.31, 128.12, 128.19, 129.10,
134.63, 149.53, 151.95, 152.23 (all for aromatic rings)
ppm. Elemental anal. for C23H26BrNO2 (C, 64.49; H, 6.12;
Br, 18.65; N, 3.27; O, 7.47); Found: C, 62.47; H,
4.52; N, 2.77.
Yellow oil; IR (KBr, cmÀ1): 3086, 3029, 2957, 2905, 2846,
2755, 2681, 1915, 1728, 1621, 1585, 1491, 1439, 1383, 1335,
1275, 1210, 1114, 1033, 919, 741; 1H-NMR (400 MHz,
CDCl3): δ = 3.16 (m, 4H, CH2-N), 3.85 (m, 4H, CH2-O),
4.00 (s, 3H, CH3-O), 4.21 (s, 2H, CH2 aliphatic), 6.77
(d, J = 8.6 Hz, 1H, CH aromatic), 7.13 (t, J = 7.9 Hz, 1H, CH
aromatic), 7.22 (m, 1H, CH aromatic), 7.29 (m, 5H, CH aromatic
)
ppm; 13C-NMR (100 MHz, CDCl3): δ = 31.2 (CH2 aliphatic),
51.4 (CH2-N), 54.9 (CH3-O), 66.6 (CH2-O), 104.7, 111.3,
112.8, 125.3, 126.8, 127.4, 127.5, 128.0, 137.2, 141.5, 144.4,
149.4 (all for aromatic rings) ppm. Elemental anal. for
C20H21NO3 (C, 74.28; H, 6.55; N, 4.33; O, 14.84); Found: C,
73.02; H, 5.99; N, 3.99.

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ABTAHI AND TAVAKOL
2.3.8 | 4h: 4-(2-(4-(Tert-butyl)benzyl)-
7-methoxybenzofuran-3-yl)morpholine
2.3.11 | 4k: 1-(2-Benzyl5-bromobenzofuran-
3-yl)piperidine
Yellow oil; IR (KBr, cmÀ1): 3054, 2957, 2905, 2852, 2816,
2752, 2674, 1906, 1693, 1620, 1580, 1491, 1437, 1382,
1275, 1206, 1113, 1074, 1034, 918, 841, 782; 1H-NMR
(400 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3):
δ = 1.34 (s, 9H, CH3 aliphatic), 3.20 (m, 4H, CH2-N), 3.88
(m, 4H, CH2-O), 4.00 (s, 3H, CH3-O), 4.21 (s, 2H, CH2 ali-
phatic), 6.78 (d, J = 7.7 Hz, 1H, CH aromatic), 7.15 (t,
J = 7.9 Hz, 1H, CH aromatic), 7.27 (d, J = 8.3 Hz, 2H, CH
aromatic), 7.31 (d, J = 7.9 Hz, 1H, CH aromatic), 7.35 (d,
J = 8.3 Hz, 2H, CH aromatic) ppm; 13C NMR (100 MHz,
CDCl3): δ = 31.4 (CH3 aliphatic), 31.7 (CH2 aliphatic), 34.4
(C aliphatic), 52.5 (CH2-N), 55.9 (CH3-O), 67.7 (CH2-O),
105.7, 112.4, 122.8, 125.4, 127.8, 128.3, 129.0, 135.2, 142.6,
145.5, 149.1, 150.8 (all for aromatic rings) ppm. Elemen-
tal anal. for C24H29NO3 (C, 75.96; H, 7.70; N, 3.69; O,
12.65); Found: C, 75.11; H, 7.26; N, 3.22.
Yellow oil; IR (KBr, cmÀ1): 3062, 3028, 2935, 2856, 2805,
2740, 2696, 1944, 1803, 1735, 1601, 1493, 1447, 1382,
1267, 1211, 1113, 1019, 860, 801, 708; 1H-NMR (400 MHz,
CDCl3): δ = 1.46 (m, 2H, CH2 aliphatic), 1.62 (m, 4H, CH2
aliphatic), 3.00 (m, 4H, CH2-N), 4.05 (s, 2H, CH2 aliphatic),
7.16 (m, 7H, CH aromatic), 7.67 (d, J = 1.9 Hz, 1H, CH
aro-
matic) ppm; 13C-NMR (100 MHz, CDCl3): δ = 24.2 (CH2
[connected to ÀCH2]), 26.8 (CH2 [connected to
ÀCH2N]), 32.5 (CH2 aliphatic), 53.7 (CH2-N), 112.9, 114.9,
122.7, 126.0, 128.6, 128.7, 128.8, 129.8, 138.1, 150.5, 152.2
(all for aromatic rings) ppm.
2.3.12 | 4l: 1-(2-(4-(Tert-butyl)benzyl)
benzofuran-3-yl)piperidine
Yellow oil; IR (KBr, cmÀ1): 3058, 3028, 2940, 2858, 2805,
2738, 2663, 1904, 1738, 1628, 1511, 1448, 1381, 1205,
1
2.3.9 | 4i: 1-(2-Benzylbenzofuran-3-yl)
piperidine
1018, 836, 750; H-NMR (400 MHz, CDCl3): δ = 1.36 (S,
9H), 1.65 (m, 4H, CH2 aliphatic), 1.78 (m, 4H, CH2 aliphatic),
3.21 (m, 4H, CH2-N), 4.20 (s, 2H, CH2 aliphatic), 7.22 (m,
2H, CH aromatic), 7.28 (d, J = 8.2 Hz, 2H, CH aromatic), 7.38
(d, J = 8.2 Hz, 2H, CH aromatic), 7.42 (m, 1H), 7.71 (m,
1H) ppm; 13C-NMR (100 MHz, CDCl3): δ = 24.4 (CH2
[connected to ÀCH2]), 26.9 (CH2 [connected to
ÀCH2N]), 31.4 (CH3 aliphatic), 31.9 (CH2 aliphatic), 34.4
(C aliphatic), 53.8 (CH2-N), 11.5, 120.1, 121.7, 123.1, 125.4,
126.7, 128.2, 130.1, 135.5, 149.1, 149.2, 153.5 (all for aro-
matic rings) ppm. Elemental anal. for C24H29NO (C,
82.95; H, 8.41; N, 4.03; O, 4.60); Found: C, 81.23; H,
7.37; N, 3.51.
Yellow oil; IR (KBr, cmÀ1): 3061, 3025, 2933, 2849, 2820,
2742, 2688, 1941, 1769, 1600, 1494, 1451, 1386, 1331,
1260, 1209, 1108, 1022, 853, 745; 1H-NMR (400 MHz,
CDCl3): δ = 1.64 (m, 2H, CH2 aliphatic), 1.76 (m, 4H, CH2-
N), 3.19 (m, 4H, CH2-O), 4.21 (s, 2H, CH2 aliphatic), 7.25
(m, 7H, CH aromatic), 7.39 (d, J = 7.5 Hz,1H, CH aromatic),
7.70 (d, J = 7.3 Hz, 1H, CH aromatic) ppm; 13C-NMR
(100 MHz, CDCl3): δ = 24.4 (CH2 [connected to ÀCH2]),
26.9 (CH2 [connected to ÀCH2N]), 32.5 (CH2 aliphatic),
53.8 (CH2-N), 111.5, 120.2, 121.8, 123.2, 126.4, 126.7,
128.5, 128.6, 130.2, 138.6, 148.9, 153.5 (all for aromatic
rings) ppm.
3 | RESULTS AND DISCUSSION
2.3.10 | 4j: 1-(2-Benzyl-5-chlorobenzofuran-
3-yl)piperidine
To find the best media, several choline chloride-based
DESs were examined to synthesize benzofuran deriva-
tives. For this purpose, a model reaction including
salicylaldehyde, morpholine, and phenylacetylene was
design to optimize the reaction conditions, and the
results were listed in Table 1. The reaction has not been
proceeded in catalyst-free conditions (Entry 1). Then, var-
ious DESs, consisting ChCl and some Lewis acids such as
CuCl2, ZnCl2, SnCl2, FeCl3, and NiCl2, were used
(Entries 2–6) at 80ꢀC in 7 h to gain green reaction media
under Lewis's acid condition.[27–30] Among these DESs,
ChCl/CuCl2 has demonstrated proper yield as a DES.
The yield was not high enough which led to using Cu
(I) or Cu (II) salts. It has been reported that Cu (I) is a
better choice than Cu (II) in recent researches. Thus, this
Yellow oil; IR (KBr, cmÀ1): 3062, 3028, 2935, 2851, 2807,
2740, 2696, 1945, 1804, 1731, 1601, 1449, 1880, 1256,
1
1211, 1106, 1020, 965, 860, 803, 710; H-NMR (400 MHz,
CDCl3): δ = 1.62 (m, 2H, CH2 aliphatic), 1.73 (m, 4H, CH2-
N), 3.11 (m, 4H, CH2-O), 4.16 (s, 2H, CH2 aliphatic), 7.15
(dd, J1 = 8.7 Hz, J2 = 2.1 Hz,1H, CH aromatic), 7.27 (m,
6H, CH aromatic), 7.62 (d, J = 2.0 Hz, 1H, CH
)
aromatic
ppm; 13C NMR (100 MHz, CDCl3): δ = 24.4 (CH2 [con-
nected to ÀCH2]), 26.7 (CH2 [connected to ÀCH2N]),
32.5 (CH2 aliphatic), 53.6 (CH2-N), 123.3, 126.4, 127.3,
128.1, 128.6, 130.2, 130.7, 138.1, 150.7, 151.8 (all for aro-
matic rings) ppm.

ABTAHI AND TAVAKOL
5 of 8
TABLE 1 The results of
optimization of the reaction conditions
for the model reactiona
Entry
Reaction media
Catalyst (mol%)
Temp (ꢀC)
Yield (%)b
Optimization of the reaction media (based on various DESs)
1
-
-
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
-
2
ChCl/CuCl2 (1:2) DES
ChCl/ZnCl2 (1:2) DES
ChCl/SnCl2 (1:2) DES
ChCl/FeCl3 (1:2) DES
ChCl/NiCl2 (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuI in ChCl/Urea (1:2) DES
CuCl in ChCl/EG (1:2) DES
CuCl2 in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
ChCl/EG (1:2) DES
EG
-
20
3
-
Trace
4
-
-
5
-
-
6
-
-
7
5
5
5
5
5
-
36
40
55
42
80
-
8
9
10
11
12
13
14
15
16
-
-
ChCl
-
-
CuI in EG
5
5
62
Trace
CuI in water
Optimization of the reaction temperature and time
c
17
18
19
20
CuI in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
5
5
5
5
40
-
60
Tracec
75c
61d
80
100
Optimization of the catalyst's amount
21
22
23
CuI in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
CuI in ChCl/EG (1:2) DES
2.5
10
15
80
80
80
48
81
77
Note: Bold items refers to the final optimized value.
Abbreviation: DES, deep eutectic solvent.
aThe model reaction: salicylaldehyde (1 mmol), morpholine (1.5 mmol), and phenylacetylene (1.2 mmol) in
ChCl/EG (0.5 mL), CuI (5 mol%), 80ꢀC, 7 h.
bIsolated yield.
cThe reaction time was 24 h.
dThe reaction time was 7 h.
salt was considered as a catalyst of the reaction. In order
to prepare a biodegradable low-cost and non-toxic media,
combination of choline chloride with ethylene glycol or
urea, as hydrogen bond donors, has been considered.
Therefore, the reaction media have been based on the
combination of ChCl/urea or ChCl/ethylene glycol DESs
with Cu (I) salts. ChCl/urea and ChCl/EG DES were cho-
sen, because they are more available, biocompatible,
good soluble of transition metal salt, and have lower
price, according to the Entries 7–11. Different Cu (I) and
Cu (II) salts have been applied with combination of
ChCl/urea or ChCl/EG DES to gain the best reaction
media. Results indicate that using CuI as a catalyst in
ChCl/EG DES has better efficiency with yield of 80%
(Entry 11). Based on the Entries 12–14, the reaction has
not been done without application of Lewis acid. There-
fore, using ChCl/EG DES with Lewis acid is necessary.
H2O (as a traditional green solvent) was also used to
investigate the reaction and compare with using DES
(Entry 16). Results of using this solvent under the same
condition have indicated less efficiency than application
of DESs. Choosing CuI as a catalyst and ChCl/EG DES as
a reaction medium (Entry 11) showed the highest yield.
So, the best time of reaction is devoted to 7 h (Entry 11),
which has showed the highest yield. In order to investi-
gate temperature effects on reaction, the reaction has
been done under 40ꢀC, 60ꢀC, and 100ꢀC, and the
reported results (Entries 17, 18, and 20) have been

6 of 8
ABTAHI AND TAVAKOL
compared with Entry 11. Decreasing temperature causes
the reaction would not to proceed and the temperature
growth reduces the yield. Therefore, the best reaction
temperature was 80ꢀC Entry 11.
Additionally, the other catalyst values (2.5, 10, and
15 mol%) were implemented under the optimal condi-
tions to compare with using 5 mol% of catalyst (Entry
11). The results are demonstrated in Entries 21–23 show
that both increasing and decreasing the amount of cata-
lyst (from 5% to 10, 15 and 2.5%) reduces the yield. There-
fore, the previous value (5%) is considered as the
optimized amount of catalyst.
In order to show the versatility of this method and
investigate the possibility of using different substituents,
12 different products were prepared, as they presented
in Scheme 2. In addition to phenylacetylene, its
4-t-butyl substituted derivative has been used for the
reaction with morpholine and pipyridine as amine
sources and various salicylaldehydes. The yields of ben-
zofurans were in the range of 70–91%. Salicylaldehydes
that contain electron-releasing substituents produced
the products in more yields. The most yield was
while
other
amines
such
as
dibutylamine,
dihexylamine, benzylamine, and aniline were used as
amine source. Additionally, the results show better
yield achievement when morpholine was used as amine
source than using pipyridine. Existence of electron
donor groups like tert-butyl on phenyl acetylene can
reduce the reaction yield, approximately.
A plausible mechanism was proposed for this reac-
tion, as it showed in Scheme 3. According to this mecha-
nism, the synthesis of disubstituted benzo furans using
CuI follows via the formation of an iminium ion from the
reaction between salicylaldehyde and secondary amine,
after the elimination of a water molecule. The organome-
tallic intermediate (consisted of C–Cu bond) is produced
via activating C–H bond from the reaction of acetylene
and CuI. Afterward, Cu–acetylide attacks to iminium ion
to produce the amine as another intermediate. Then, oxy-
gen atom attacks as a nucleophile to sp carbon and forms
a 5-membered ring through an intermolecular reaction.
Finally, an isomerization was expected to prepare the
desired product. In addition to the role of solvent,
the employed DES stabilize highly polar intermediates
and transition states because of its ionioc nature. In fact,
in the absence of DES, the reaction has been performed
slowly. In addition, the hydroxy groups of ethelene glycol
observed
in
the
reactions
with
2-hydroxy-
3-methoxybenzaldehyde, as aldehyde source. It must be
noticed that there was no improvement in the reaction
SCHEME 2 The general reaction
conditions and produced benzofuran
derivatives

ABTAHI AND TAVAKOL
7 of 8
SCHEME 3 The plausible proposed
mechanism for the reaction
TABLE 2 Comparisons of ChCl-EG/CuI with other recent reports of reaction condition for the synthesis of benzofuran
Entry Catalyst
Reaction conditions
Time (h) Catalyst amount Yield (%) Ref
1
2
3
4
5
6
7
HS-CuO
Neat/110ꢀC
1.5
4 mg
88–95
79–90
88–93
40–77
46–86
52–90
70–91
Purohit et al.[1]
Cu2ONPs
Neat/K2CO3/TBAB/100ꢀC 1.75
20 mol%
25 mg
Mahmoodi and Jazayri[21]
Sadjadi et al.[23]
Nguyen and Li[6]
Li et al.[5]
h-Fe2O@SiO2-IL/Ag H2O/r.t/ultrasound
0.5
16
3
CuI
CuI
CuI
CuI
CH3CN/reflux
Toluene/110ꢀC
[Bmim]PF6/80ꢀC
ChCl-EG/80ꢀC
30 mol%
20 mol%
10 mol%
5 mol%
6
Zhang et al.[22]
7
This work
make hydrogen bond with all possible ingredients, which
could be useful for the better performance. The chloride
ion, existed in DES, also could act as a weak base for
deprotonation of species, when is needed.
In summary, 12 different derivatives of benzofuran have
been prepared during 7-h stirring at 80ꢀC with 70–91%
yields.
In order to show the applicability of the synthesis
method, the results have been compared with the other
related studies. The results in Table 2 show that the the
presented method has several advantages such as using
non-toxic solvents, inexpensive and available catalyst,
comparing with the previous reports. Additionally, using
little mass amount of catalyst is another advantage of this
method.
ACKNOWLEDGMENT
The present study has been partially supported by
Isfahan University of technology.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of
interest.
ORCID
Hossein Tavakol https://orcid.org/0000-0002-3296-9575
4 | CONCLUSION
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