DABCO-catalyzed multi-component domino reactions for the one-pot efficient synthesis of diverse and densely functionalized benzofurans in water

Article abstract of DOI:10.1007/s11164-016-2726-1

An efficient, three-component strategy for the improved synthesis of a pharmaceutically interesting diverse kind of multi-functionalized benzofurans via one-pot two-step domino protocol with high diastereoselectivity in excellent yields has been established. The synthesis was achieved by reacting phenacyl bromides, N-heterocycles, aromatic aldehydes, and cyclic 1,3-dicarbonyl compounds in the presence of a catalytic amount of DABCO (1,4-diazabicyclo[2.2.2]octane) as an inexpensive, impressive, and readily available catalyst in water under reflux. In this process in total three new bonds (two C–C and one C–O) form in one pot. Short reaction time, excellent yields, no chromatographic purification, and evasion of environmentally hazardous or toxic catalysts and organic solvents in the entire reaction process may make this protocol very useful for academia and industry.

Full text of DOI:10.1007/s11164-016-2726-1

Res Chem Intermed
DOI 10.1007/s11164-016-2726-1
DABCO-catalyzed multi-component domino reactions
for the one-pot efficient synthesis of diverse and densely
functionalized benzofurans in water
Sajedeh Golchin1 Mohammad Hossein Mosslemin1
•
•
Afshin Yazdani-Elah-Abadi2 Nasim Shams2
•
Received: 5 July 2016 / Accepted: 31 August 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract An efficient, three-component strategy for the improved synthesis of a
pharmaceutically interesting diverse kind of multi-functionalized benzofurans via
one-pot two-step domino protocol with high diastereoselectivity in excellent yields
has been established. The synthesis was achieved by reacting phenacyl bromides, N-
heterocycles, aromatic aldehydes, and cyclic 1,3-dicarbonyl compounds in the
presence of a catalytic amount of DABCO (1,4-diazabicyclo[2.2.2]octane) as an
inexpensive, impressive, and readily available catalyst in water under reflux. In this
process in total three new bonds (two C–C and one C–O) form in one pot. Short
reaction time, excellent yields, no chromatographic purification, and evasion of
environmentally hazardous or toxic catalysts and organic solvents in the entire
reaction process may make this protocol very useful for academia and industry.
Keywords Multicomponent domino reactions (MDRs) Á One-pot synthesis Á
Environmentally-friendly Á DABCO Á Benzofuran
Introduction
Synthesis of polyfunctionalized heterocyclic compounds from readily available
starting materials in a cost and time effective manner has received significant
attention in organic synthesis due to their extensive applications in pharmaceuticals,
agrochemicals and in materials sciences [1–4]. In this area, multi-component
domino reactions (MDRs), in which more than two components are combined in a
single synthetic operation, have been extensively used as a powerful strategy in the
&
Nasim Shams
n.shams1360@gmail.com
1
2
Department of Chemistry, Yazd Branch, Islamic Azad University, P.O. Box 89195-155,
Yazd, Iran
Young Researchers and Elite Club, Yazd Branch, Islamic Azad University, Yazd, Iran
123

S. Golchin et al.
synthesis of complex heterocyclic molecules due to their advantages such as higher
productivity, simple procedures, facile execution, lower costs, minimum waste
production, structural diversity, shorter reaction times, environmentally-friendli-
ness, atom economy, high selectivity and allowing savings of both solvents and
reagents [5–10].
On the other hand, replacement of hazardous solvents with environmentally
benign solvents [11–15] is one of the major focus areas of green chemistry. Organic
solvents used in most of the synthetic organic chemistry evaporate into the
atmosphere with destructive effects on the environment and ozone layer [16]. Thus,
aqueous phase organic synthesis has attracted the attention of chemists as it
overcomes the harmful effects associated with the organic solvents and is
environmentally benign. Moreover, using water as the medium, surfactants can be
used to build micelles and provide better chemical yields and shorter reaction times
due to its strong hydrogen bonding ability, hydrophobic effects and high polarity
[17–19].
Benzofurans and its derivatives are an important category of oxygen-containing
heterocycles owing to their wide existence in natural products, pharmaceuticals and
biologically active compounds [20–24]. Benzofurans are integral to a large number
of drug substances with activities including anticoagulant, insecticide, anthel-
minthic, hypnotic, antifungal, and HIV protease inhibition properties [25, 26]. Some
benzofurans serve as versatile synthetic intermediates that can synthesize various
useful compounds [27–30].
Therefore, considering the importance of benzofuran derivatives, and in
continuation of our ongoing program for the synthesis of heterocyclic compounds
[31–35], herein, we report the diastereoselective formation of polyfunctionalized
benzofuran derivatives 6 through a domino, one-pot, multi-component condensation
reaction between phenacyl bromides 1, N-heterocycles 2, aromatic aldehydes 4 and
cyclic 1,3-dicarbonyl compounds 5 in the presence of DABCO as a high reactive,
non-toxic, and easy to handle catalyst in water under reflux conditions (Scheme 1).
Experimental
General
All melting points were determined with an Electrothermal 9100 apparatus.
Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyser at
the analytical laboratory of Islamic Azad University, Yazd branch. Mass spectra
were recorded on a Finnigan-Mat 8430 mass spectrometer operating at an ionisation
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer (1H NMR
at 400 Hz, 13C NMR at 100 Hz) in CDCl3 using TMS as an internal standard.
Chemical shifts (d) are given in ppm and coupling constants (J) are given in Hz. The
chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and
were used without further purification.
123

DABCO-catalyzed multi-component domino reactions for the…
Scheme 1 One-pot, domino multi-component synthesis of polyfunctionalized benzofuran derivatives in
the presence of DABCO as an efficient solid base catalyst
General experimental procedure for the synthesis of benzofuran derivatives
(6a–w)
At first, phenacyl bromide 1 (1 mmol) and isoquinoline 2 (1 mmol) were added to a
25-mL round-bottomed flask containing water (10 mL) as solvent. The flask was
fitted with a condenser, and the resulting mixture was stirred at room temperature.
After the required time (2 min) for the formation of corresponding salt (white solid)
3, aromatic aldehyde 4 (1 mmol), cyclic 1,3-dicarbonyl compounds 5 (1 mmol) and
DABCO (20 mol%) as catalyst were added into the reaction mixture and were
heated under reflux conditions for the times reported in Table 2. Upon completion
of the reaction, monitored by TLC, the solid product was filtered and was washed
twice with H2O (2 9 5 mL), dried, and subsequently recrystallized from hot
ethanol. The analytical and spectroscopic data for the unknown compounds are
represented below:
2-(4-Chlorobenzoyl)-6,6-dimethyl-3-(4-nitrophenyl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6b)
White powder; yield: 0.404 g (95 %); m.p. 199–202 °C; IR (KBr) (mmax, cm-1):
1
1694 (C=O), 1513, 1395, (NO2); HNMR (400 MHz, CDCl3): d = 2.16 (2H, m,
CH2), 2.35 (2H, m, CH2), 2.71 (2H, m, CH2), 4.72 (1H, d, J = 4.8 Hz, CH), 5.76
123

S. Golchin et al.
(1H, d, J = 4.8 Hz, CH), 7.44 (2H, d, J = 8.8 Hz, CH), 7.49 (2H, d, J = 8.8 Hz,
CH), 7.82 (2H, d, J = 8.8 Hz, 2CH), 8.23 (2H, d, J = 8.8 Hz, 2CH) ppm; 13C
NMR (100 MHz, CDCl3): d = 21.12 (CH2), 23.73 (CH2), 37.81 (CH2), 43.85 (CH),
89.07 (CH), 114.00 (C), 118.46 (C), 123.52 (C), 124.67 2(CH), 128.42 (2CH),
129.23 (2CH), 131.03 (2CH), 140.65 (C), 149.63 (C), 177.26 (C), 192.44, 194.23
(2C=O); MS (m/z, %): 425 (M?, 9); Anal. Calcd for C23H20ClNO5: C, 64.87; H,
4.73; N, 3.29 %. Found: C, 67.59; H, 4.61; N, 3.44 %.
2-(4-Chlorobenzoyl)-3-(4-fluorophenyl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6c)
White powder; yield: 0.337 g (91 %); m.p. 162–164 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O); HNMR (400 MHz, CDCl3): d = 2.19 (2H, m, CH2), 2.34 (2H, m,
CH2), 2.72 (2H, m, CH2), 4.47 (1H, 2d, J = 4.8 Hz, CH), 5.77 (1H, 2d, J = 4.8 Hz,
CH), 7.07 (2H, t, J = 8.8 Hz, 2CH), 7.22 (2H, dd, J = 8.8 Hz, J = 5.2 Hz, 2CH),
7.47 (2H, d, J = 8.8 Hz, 2CH), 7.79 (2H, d, J = 8.8 Hz, 2CH), ppm; 13C NMR
(100 MHz, CDCl3): d = 21.70 (CH2), 23.88 (CH2), 36.76 (CH2), 48.01 (CH), 91.42
(CH), 116.01 (d, 2JCF = 21.0 Hz, 2CHortho), 116.32 (C), 128.92 (d, 3JCF = 8.0 Hz,
4
2CHmeta), 129.34 (2CH), 130.37 (2CH), 131.64 (C), 136.77 (d, JCF = 3.0 Hz,
1
Cpara), 140.92 (C), 162.21 (d, JCF = 244.0 Hz, Cipso), 177.09 (C), 191.63, 194.28
(2C=O); MS (m/z, %): 370 (M?, 4); Anal. Calcd for C21H16ClFO3: C, 68.02; H,
4.35 %. Found: C, 67.87; H, 4.51 %.
2-(4-Chlorobenzoyl)-3-(4-cyanophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6d)
White powder; yield: 0.360 g (89 %); m.p. 156–158 °C; IR (KBr) (mmax, cm-1):
2260 (CN), 1688 (C=O); 1HNMR (400 MHz, CDCl3): d = 2.15 (2H, m, CH2), 2.37
(2H, m, CH2), 2.71 (2H, m, CH2), 4.64 (1H, d, J = 4.8 Hz, CH), 5.76 (1H, d,
J = 4.8 Hz, CH), 7.38 (2H, d, J = 8.8 Hz, 2CH), 7.49 (2H, d, J = 8.8 Hz, 2CH),
7.67 (2H, d, J = 8.8 Hz, 2CH), 7.81 (2H, d, J = 8.8 Hz, 2CH) ppm; 13C NMR
(100 MHz, CDCl3): d = 21.65 (CH2), 23.88 (CH2), 36.67 (CH2), 48.12 (CH), 90.83
(CH), 111.63 (C), 115.72 (C), 118.59 (CN), 128.30 (2CH), 129.42 (2CH), 130.44
(2CH), 131.66 (C), 132.92 (2CH), 141.12 (C), 146.28 (C), 177.34 (C), 191.14,
194.13 (2C=O); MS (m/z, %): 405 (M?, 7); Anal. Calcd for C24H20ClNO3: C, 71.02;
H, 4.97; N, 3.45 %. Found: C, 71.26; H, 4.82;N, 3.70 %.
2-(4-Chlorobenzoyl)-3-(thiophen-2-yl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6e)
White powder; yield: 0.301 g (84 %); m.p. 173–175 °C; IR (KBr) (mmax, cm-1):
1688 (C=O).1HNMR (400 MHz, CDCl3): d = 2.14 (2H, m, CH2), 2.37 (2H, m,
CH2), 2.70 (2H, m, CH2), 4.81 (1H, d, J = 4.8 Hz, CH), 5.86 (1H, d, J = 4.8 Hz,
CH), 6.95 (1H, m, CH), 6.98 (1H, d, J = 5.2 Hz, CH), 7.24 (1H, d, J = 5.2 Hz,
CH), 7.49 (2H, d, J = 8.8 Hz, 2CH), 7.88 (2H, d, J = 8.8 Hz, 2CH) ppm; 13C
NMR (100 MHz, CDCl3): d = 21.61 (CH2), 23.91 (CH2), 36.80 (CH2), 43.76 (CH),
123

DABCO-catalyzed multi-component domino reactions for the…
91.16 (CH), 115.87 (C), 124.87 (CH), 125.20 (CH), 127.33 (CH), 129.35 (2CH),
130.46 (2CH), 131.61 (C), 140.93 (C), 144.57 (C), 177.26 (C), 191.37, 194.31
(2C=O); MS (m/z, %): 358 (M?, 3); Anal. Calcd for C19H15ClO3S: C, 63.59; H,
4.21; S, 8.94 %. Found: C, 63.66; H, 4.01; S, 8.68 %.
(E)-2-(4-Chlorobenzoyl)-3-styryl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (6f)
White powder; yield: 0.310 g (82 %); m.p. 151–154 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O); HNMR (400 MHz, CDCl3): d = 2.18 (3H, m, CH2), 2.37 (3H, m,
CH2), 2.71 (3H, m, CH2), 4.10 (1H, m, CH), 5.75 (1H, d, J = 4.8 Hz, CH), 6.15
(1H, dd, J = 16.0 Hz, 2.8 Hz, CH), 6.75 (1H, dd, J = 16.0 Hz, 8.0 Hz, CH), 7.42
(2H, d, J = 8.8 Hz, 2CH), 7.47–7.61 (5H, m, 5CH), 7.87 (2H, d, J = 8.8 Hz, 2CH),
ppm; 13C NMR (100 MHz, CDCl3): d = 21.60 (CH2), 23.83 (CH2), 36.68 (CH2),
38.70 (CH), 88.16 (CH), 114.96 (C), 115.70 (CH), 127.30 (2CH), 128.06 (2CH),
129.42 (2CH), 130.03 (CH), 130.41 (2CH), 132.88 (2CH), 136.05 (C), 137.79 (C),
141.04 (C), 177.33 (C), 191.15, 194.07 (2C=O); MS (m/z, %): 378 (M?, 7); Anal.
Calcd for C23H19ClO3: C, 72.92; H, 5.06 %. Found: C, 72.74; H, 5.30 %.
4-(2-(4-Chlorobenzoyl)-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-3-yl)benzaldehyde
(6g)
White powder; yield: 0.331 g (87 %); m.p. 206 °C; IR (KBr) (mmax, cm-1): 1690
(C=O); 1399, 1520 (NO2).1H NMR (400 MHz, CDCl3): d = 2.17 (3H, m, CH2),
2.35 (3H, m, CH2), 2.72 (3H, m,CH2), 4.62(H, d, J = 4.8 Hz, CH), 5.81 (H, d,
J = 4.8 Hz, CH), 7.43 (2H, d, J = 8.8 Hz, 2CH), 7.46 (2H, d, J = 8.8 Hz, 2CH),
7.80 (2H, d, J = 8.8 Hz, 2CH), 7.89 (2H, d, J = 8.8 Hz, 2CH), 10.01 (1H, s, CHO)
ppm; 13C NMR (100 MHz, CDCl3): d = 21.66 (CH2), 23.86 (CH2), 36.68 (CH2),
48.42 (CH), 90.93 (CH), 115.95 (C), 128.16 (2CH), 129.38 (2CH), 130.43 (2CH),
130.58 (2CH), 131.64 (C), 135.81 (C), 141.02 (C), 147.76 (C), 177.41 (C), 191.30,
191.74, 194.25 (3C=O); MS (m/z, %): 380 (M?, 5); Anal. Calcd for C22H17ClO4: C,
69.39; H, 4.50 %. Found: C, 69.60; H, 4.27 %.
2-(4-Bromobenzoyl)-3-(3-chloro-4-nitrophenyl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6h)
White powder; yield: 0.422 g (89 %); m.p. 194–196 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O), 1520, 1380 (NO2); HNMR (400 MHz, CDCl3): d = 2.19 (2H, m,
CH2), 2.38 (2H, m, CH2), 2.70 (2H, m, CH2), 4.73 (1H, d, J = 4.8 Hz, CH), 5.74
(1H, d, J = 4.8 Hz, CH), 7.47 (1H, dd, J = 8.4 Hz, 2 Hz, CH), 7.51 (2H, d,
J = 8.8 Hz, 2CH), 7.77 (1H, d, J = 8.8 Hz, CH), 7.86 (2H, d, J = 8.8 Hz, 2CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 21.62 (CH2), 23.89 (CH2), 36.64 (CH2),
46.99 (CH), 90.99 (CH), 115.78 (C), 124.27 (CH), 126.38 (C), 128.73 (C), 128.99
(C), 129.48 (2CH), 130.52 (2CH), 131.70 (C), 132.44 (CH), 132.66 (CH), 141.47
(C), 177.40 (C), 190.92, 194.11 (2C=O); MS (m/z, %): 474 (M?, 11); Anal. Calcd
for C21H15BrClNO5: C, 52.91; H, 3.17; N, 2.94 %. Found: C, 53.12; H, 3.38;N,
2.69 %.
123

S. Golchin et al.
2-(4-Bromobenzoyl)-3-(2-fluorophenyl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6i)
White powder, yield: 0.352 g (85 %); m.p.171–172 °C; IR (KBr) (mmax, cm-1):
1
1694 (C=O); HNMR (400 MHz, CDCl3): d = 2.15(2H, m, CH2), 2.36(2H, m,
CH2), 2.69 (2H, m, CH2), 4.79 (1H, d, J = 5.2 Hz, CH), 5.83 (1H, d, J = 5.2 Hz,
CH), 7.08 (1H, t, J = 9.2 Hz, CH), 7.15 (1H, t, J = 7.6 Hz, CH), 7.22 (1H, t,
J = 7.6 Hz, CH), 7.30 (1H, m, CH), 7.45 (2H, d, J = 8.8 Hz, 2CH), 7.82 (2H, d,
J = 8.8 Hz, 2CH) ppm; 13C NMR (100 MHz, CDCl3): d = 21.78 (CH2), 23.93
(CH2), 36.77 (CH2), 42.63 (d, J = 3 Hz, CH), 89.97 (CH), 114.71(C), 115.13 (d,
J = 22 Hz, Cortho), 124.68 (d, J = 3 Hz, Cpara), 127.46 (d, J = 13 Hz, Cortho),
129.25 (2CH), 129.40 (d, J = 8 Hz, Cmeta), 129.58 (d, J = 4 Hz, Cmeta), 130.42
(2CH), 131.84 (C), 140.79 (C), 160.62 (d, J = 246 Hz, Cipso), 177.39 (C), 191.45,
194.22 (2C=O); MS (m/z, %): 414 (M?, 7); Anal. Calcd for C21H16BrFO3: C, 60.74;
H, 3.88 %. Found: C, 60.49; H, 4.10 %.
2-(4-Bromobenzoyl)-3-(2-bromophenyl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6j)
White powder, yield: 0.421 g (89 %); m.p. 180–182 °C; IR (KBr) (mmax, cm-1):
1
2265 (CN), 1688 (C=O); HNMR (400 MHz, CDCl3): d = 2.16 (2H, m, CH2),
2.40 (2H, m, CH2), 2.65 (2H, m, CH2), 5.12 (1H, 2d, J = 4.8 Hz, CH), 5.76
(1H, 2d, J = 4.8 Hz, CH), 7.17 (2H, m, 2CH), 7.32 (1H, t, J = 8 Hz, CH), 7.46
(2H, d, J = 8.8 Hz, 2CH), 7.57 (1H, d, J = 8.0 Hz, CH), 7.85 (2H, d,
J = 8.8 Hz, 2CH) ppm; 13C NMR (100 MHz, CDCl3): d = 21.26 (CH2), 24.00
(CH2), 36.80 (CH2), 47.20 (CH),89.88 (CH), 115.67 (C), 123.83 (C), 127.11 (C),
128.07 (CH), 129.18 (CH), 129.24 (2CH), 130.53 (2CH), 132.18 (C), 133.41
(CH), 139.85 (C), 140.71 (C), 177.23 (C), 190.90, 194.04 (2C=O); MS (m/z, %):
473 (M?, 2); Anal. Calcd for C21H16Br2O3: C, 52.97; H, 3.39 %. Found: C,
52.81; H, 3.54 %.
2-(4-Bromobenzoyl)-3-(4-hydroxyphenyl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6k)
White powder; yield: 0.346 g (84 %); m.p. 147–149 °C; IR (KBr) (mmax, cm-1):
1
3325 (OH), 1688 (C=O); HNMR (400 MHz, CDCl3): d = 2.19(3H,m, CH2), 2.35
(3H,m, CH2), 2.71 (3H,m, CH2), 4.65 (1H, d, J = 4.8 Hz, CH), 5.76 (1H, d,
J = 4.8 Hz, CH), 6.64 (1H, b, OH), 7.20 (2H, d, J = 8.8 Hz, 2CH), 7.49 (2H, d,
J = 8.8 Hz, 2CH), 7.68 (2H, d, J = 8.8 Hz, 2CH), 7.81(2H, d, J = 8.8 Hz, 2CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 21.65 (CH2), 23.88 (CH2), 36.68 (CH2),
48.10 (CH), 90.82 (CH), 114.98 (C), 115.69 (2CH), 129.40 (2CH), 130.46 (2CH),
131.70 (C), 132.90 (2CH), 136.03 (C), 141.07 (C), 156.11 (C), 177.35 (C), 191.18,
194.11 (2C=O); MS (m/z, %): 412 (M?, 6); Anal. Calcd for C21H17BrO4: C, 61.03;
H, 4.15 %. Found: C, 60.82; H, 4.22 %.
123

DABCO-catalyzed multi-component domino reactions for the…
2-(4-Bromobenzoyl)-3-(naphthalen-1-yl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one
(6l)
White powder; yield: 0.397 g (89 %); m.p. 169–170 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O); HNMR (400 MHz, CDCl3): d = 2.20 (2H, m, CH2), 2.41 (2H, m,
CH2), 2.72 (2H, m, CH2), 4.73 (1H, d, J = 4.8 Hz, CH), 5.80 (1H, d, J = 4.8 Hz,
CH), 7.36 (H, m, CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.49 (3H, m, 3CH), 7.81 (2H,
d, J = 8.8 Hz, 2CH), 7.89 (1H, d, J = 8.0 Hz, CH), 8.01 (1H, d, J = 8 Hz, CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 21.77 (CH2), 24.05 (CH2), 36.90 (CH2),
47.09 (CH), 91.21 (CH), 116.17 (C), 123.22 (CH), 125.66 (CH), 125.86 (CH),
126.47 (CH), 127.55 (CH), 127.84 (CH), 128.27 (CH), 128.98 (C), 129.14 (2CH),
130.80 (2CH), 131.25 (C), 132.21 (C), 134.21 (C), 140.70 (C), 176.71 (C), 191.89,
194.42 (2C=O); MS (m/z, %): 446 (M?, 9); Anal. Calcd for C25H19BrO3: C, 67.13;
H, 4.28 %. Found: C, 67.37; H, 4.35 %.
2-(4-Chlorobenzoyl)-6,6-dimethyl-3-(4-nitrophenyl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6m)
White powder; yield: 0.404 g (95 %); m.p. 207–210 °C; IR (KBr) (mmax, cm-1):
1
1690 (C=O), 1521, 1390 (NO2); H NMR (400 MHz, CDCl3): d = 1.17 (3H, s,
CH3), 1.18 (3H, s, CH3), 2.24, 2.31 (AB system, J = 16.0 Hz, 2H, CHAHB-
C(CH3)2), 2.58, 2.63 (AB system, J = 16.0 Hz, 2H, CHAHBCO), 4.69 (1H, 2d,
J = 4.8 Hz, CH), 5.81 (1H, 2d, J = 4.8 Hz, CH), 7.44 (2H, d, J = 8.8 Hz, 2CH),
7.49 (2H, d, J = 8.8 Hz, 2CH), 7.82 (2H, d, J = 8.8 Hz, 2CH), 8.24 (2H, d,
J = 8.8 Hz, 2CH) ppm; 13C NMR (100 MHz, CDCl3): d = 28.40 (CH3), 28.95
(CH3), 34.43 (C), 37.65 (CH2), 47.91 (CH), 51.02 (CH2CO), 90.94 (CH), 114.44
(C), 119.09 (C), 123.98 (C), 124.48 (2CH), 128.36 (2CH), 129.44 (2CH), 130.39
(2CH), 141.16 (C), 148.27 (C), 176.28 (C), 191.73, 196.39 (2C=O); MS (m/z, %):
425 (M?, 3); Anal. Calcd for C23H20ClNO5: C, 64.87; H, 4.73; N, 3.29 %. Found:
C, 65.08; H, 4.98;N, 3.01 %.
2-(4-Chlorobenzoyl)-3-(4-fluorophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6n)
White powder; yield: 0.338 g (85 %); m.p. 166–168 °C; IR (KBr) (mmax
,
cm-1):1689 (C=O); 1HNMR (400 MHz, CDCl3): d = 1.18 (3H, s, CH3), 1.19
(3H, s, CH3), 2.22, 2.29 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.52, 2.60
(AB system, J = 16.0 Hz, 2H, CHAHBCO), 4.46 (1H, 2d, J = 4.8 Hz, CH), 5.77
(2H, 2d, J = 4.8 Hz, 2CH), 7.05 (2H, t, J = 8.8 Hz, 2CH), 7.22 (2H, dd,
J = 8.8 Hz, J = 5.2 Hz, 2CH), 7.45 (2H, d, J = 8.8 Hz),7.78 (2H, d, J = 8.8 Hz),
ppm; 13C NMR (100 MHz, CDCl3): d = 28.39 (CH3), 29.17 (CH3), 34.30 (C),
37.93 (CH2), 42.76 (d, 3JCF = 2.0 Hz, CH), 51.32 (CH2CO), 91.40 (CH), 115.99 (d,
2
2JCF = 21.0 Hz, Cortho), 116.29 (C), 128.93 (d, JCF = 8.0 Hz, Cmeta), 129.32
4
(2CH), 130.37 (2CH), 131.64 (C), 136.78 (d, JCF = 4.0 Hz, Cpara), 140.88 (C),
1
161.22 (d, JCF = 246.0 Hz, Cipso), 177.09 (C), 191.63, 194.26 (2C=O); MS (m/z,
123

S. Golchin et al.
%): 398 (M?, 7); Anal. Calcd for C23H20ClFO3: C, 69.26; H, 5.05 %. Found: C,
69.08; H, 4.80 %.
4-(2-(4-Chlorobenzoyl)-6,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-3-
yl)benzonitrile (6o)
White powder; yield: 0.360 g (89 %); m.p. 183–185 °C; IR (KBr) (mmax, cm-1):
2265 (CN), 1688 (C=O); 1H NMR (400 MHz, CDCl3): d = 1.18 (3H, s, CH3), 1.18
(3H, s, CH3), 2.22, 2.28 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.54, 2.60
(AB system, J = 16.0 Hz, 2H, CHAHBCO), 4.62 (1H, 2d, J = 4.8 Hz, CH), 5.87
(1H, 2d, J = 4.8 Hz, CH), 7.39 (2H, d, J = 8.8 Hz, 2CH), 7.49 (2H, d, J = 8.8 Hz,
2CH), 7.68 (2H, d, J = 8.8 Hz, 2CH), 7.81 (2H, d, J = 8.8 Hz, 2CH) ppm; 13C
NMR (100 MHz, CDCl3): d = 28.42(CH3), 28.97 (CH3), 34.43 (C), 37.64 (CH2),
48.17 (CH), 51.03 (CH2CO), 91.02 (CH), 111.66 (C), 114.40(C), 118.57 (CN),
128.26 (2CH), 129.42 (2CH), 130.40 (2CH), 131.60 (C), 132.96 (2CH), 141.10 (C),
146.33 (C), 176.37 (C), 191.10, 193.45 (2C=O); MS (m/z, %): 405 (M?,12); Anal.
Calcd for C24H20ClNO3: C, 71.02; H, 4.97; N, 3.45 %. Found: C, 69.79; H, 5.19;N,
3.18 %.
2-(4-Chlorobenzoyl)-3-(2-chlorophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6p)
White powder; yield: 0.393 g (95 %); m.p. 140–141 °C; IR (KBr) (mmax, cm-1):
1
1696 (C=O); HNMR (400 MHz, CDCl3): d = 1.17 (3H, s, CH3), 1.21 (3H, s,
CH3), 2.25, 2.32 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.48, 2.57 (AB
system, J = 16.0 Hz, 2H, CHAHBCO), 5.09 (1H, 2d, J = 4.8 Hz, CH), 5.80 (1H,
2d, J = 4.8 Hz, CH),7.16 (1H, t, J = 8.0 Hz, CH), 7.20 (1H, d, J = 8.0 Hz, CH),
7.33 (1H, t, J = 8.0 Hz, CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.57 (1H, d,
J = 8.0 Hz, CH), 7.84 (2H, d, J = 8.8 Hz, 2CH), 7.84 (2H, d, J = 8.8 Hz, 2CH)
ppm; 13C NMR (100 MHz, CDCl3): d = 28.59 (CH3), 29.02 (CH3), 34.21 (C),
37.74 (CH2), 47.28(CH), 51.17 (CH2CO), 90.20 (CH), 114.52 (C), 123.78 (C),
127.06 (C), 128.12 (CH), 129.12 (CH), 129.26 (2CH), 130.47 (2CH), 132.07 (C),
133.41 (CH), 140.03 (C), 140.71 (C), 176.27 (C), 190.93, 193.37 (2C=O); MS (m/z,
%): 414 (M?, 4); Anal. Calcd for C23H20Cl2O3: C, 66.52; H, 4.85 %. Found: C,
66.79; H, 4.81 %.
2-(4-Chlorobenzoyl)-6,6-dimethyl-3-(4-hydroxyphenyl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6q)
White powder; yield: 0.321 g (81 %); m.p. 155–157 °C; IR (KBr) (mmax, cm-1):
3295 (OH), 1683 (C=O); 1HNMR (400 MHz, CDCl3): d = 1.18 (3H, s, CH3), 1.19
(3H, s, CH3), 2.22, 2.28 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.54, 2.60
(AB system, J = 16.0 Hz, 2H, CHAHBCO), 4.62 (1H, d, J = 4.8 Hz, CH), 5.78
(1H, d, J = 4.8 Hz, CH), 6.58 (1H, b, OH), 7.10 (2H, d, J = 8.8 Hz, 2CH), 7.48
(2H, d, J = 8.8 Hz, 2CH), 7.68 (2H, d, J = 8.8 Hz, 2CH), 7.80 (2H, d, J = 8.8 Hz,
2CH), ppm; 13C NMR (100 MHz, CDCl3): d = 28.42 (CH3), 28.96 (CH3), 34.42
123

DABCO-catalyzed multi-component domino reactions for the…
(C), 37.64 (CH2), 48.18 (CH), 51.03 (CH2CO), 91.02 (CH), 114.26 (C), 115.40
(2CH), 129.42 (2CH), 130.40 (2CH), 131.62 (C), 132.95 (2CH), 134.26 (C), 141.09
(C), 155.04 (C), 176.34 (C), 191.10, 193.41 (2C=O); MS (m/z, %): 396 (M?, 4);
Anal. Calcd for C23H21ClO4: C, 69.61; H, 5.33 %. Found: C, 69.80; H, 5.14 %.
2-(4-Chlorobenzoyl)-6,6-dimethyl-3-(thiophen-2-yl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6r)
White powder; yield: 0.313 g (81 %); m.p. 177–180 °C; IR (KBr) (mmax, cm-1):
1
1683 (C=O); HNMR (400 MHz, CDCl3): d = 1.18, (3H, s, CH3), 1.22 (3H, s,
CH3), 2.24, 2.29 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.53, 2.61 (AB
system, J = 16.0 Hz, 2H, CHAHBCO), 4.80 (1H, d, J = 4.8 Hz, CH), 5.86 (1H, d,
J = 4.8 Hz, CH), 6.95 (1H, m, CH), 6.98 (1H, d, J = 5.2 Hz, CH), 7.25 (1H, d,
J = 5.2 Hz, CH), 7.49 (2H, d, J = 8.8 Hz, 2CH), 7.88 (2H, d, J = 8.8 Hz, 2CH),
ppm; 13C NMR (100 MHz, CDCl3): d = 28.17 (CH3), 29.23 (CH3), 34.28 (C),
37.64 (CH2), 43.79 (CH), 51.14 (CH2CO), 91.40 (CH), 114.48 (C), 124.92 (CH),
125.24 (CH), 127.32 (CH), 129.37 (2CH), 130.45 (2CH), 131.57 (C), 140.92 (C),
144.72 (C), 176.40 (C), 191.33, 193.44 (2C=O); MS (m/z, %): 386 (M?, 9); Anal.
Calcd for C21H19ClO3S: C, 65.19; H, 4.95; S, 8.29 %. Found: C, 64.93; H, 4.81; S,
8.57 %.
2-(4-Chlorobenzoyl)-6,6-dimethyl-3-(naphthalen-1-yl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6s)
White powder; yield: 0.383 g (89 %); m.p. 159–161 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O); HNMR (400 MHz, CDCl3): d = 1.20 (3H, s, CH3), 1.26 (3H, s,
CH3), 2.31 (2H, m, CH2), 2.59 (2H, m, CH2), 4.63 (1H, d, J = 4.8 Hz, CH), 5.82
(1H, d, J = 4.8 Hz, CH), 7.37 (H, m, CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.48
(3H, m, 3CH), 7.82 (2H, d, J = 8.8 Hz, 2CH), 7.91 (1H, d, J = 8.0 Hz, CH), 7.97
(1H, d, J = 8.0 Hz, CH) ppm; 13C NMR (100 MHz, CDCl3): d = 28.67 (CH3),
29.13 (CH3), 34.32 (C), 37.81 (CH2), 47.06 (CH), 51.28 (CH2CO), 91.40 (CH),
115.01 (C), 123.26 (CH) 125.66 (CH), 125.88 (CH), 126.46 (CH), 127.31 (CH),
127.68 (CH),128.34 (CH), 129.02 (C), 129.17 (2CH), 130.77 (2CH), 131.24 (C),
132.13 (C), 134.23 (C), 140.71 (C), 175.68 (C), 191.88, 193.64 (2C=O); MS (m/z,
%): 430 (M?, 5); Anal. Calcd for C27H23ClO3: C, 75.25; H, 5.38 %. Found: C,
75.33; H, 5.56 %.
2-(4-Bromobenzoyl)-3-(4-bromophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6t)
White powder; yield: 0.446 g (89 %); m.p. 135–136 °C; IR (KBr) (mmax, cm-1):
1
1688 (C=O); HNMR (400 MHz, CDCl3): d = 1.06 (3H, s, CH3), 1.08 (3H, s,
CH3), 2.11, 2.17 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.53, 2.62 (AB
system, J = 16.0 Hz, 2H, CHAHBCO), 4.62 (1H, d, J = 4.8 Hz, CH), 6.37 (1H, d,
J = 4.8 Hz, CH),7.48 (2H, d, J = 8.8 Hz, 2CH), 7.63 (2H, d, J = 8.8 Hz, 2CH),
7.87 (2H, d, J = 8.8 Hz, 2CH), 8.22 (2H, d, J = 8.8 Hz, 2CH), ppm; 13C NMR
123

S. Golchin et al.
(100 MHz, CDCl3): d = 27.81 (CH3), 28.10 (CH3), 34.02 (C), 36.57 (CH2), 47.00
(CH), 50.44 (CH2CO), 89.96 (CH), 113.60 (C), 123.81 (2CH), 128.56 (C), 128.89
(2CH), 129.07 (CH), 130.85 (2CH), 131.29 (C), 139.14 (C), 146.67 (C), 176.59 (C),
192.03, 192.59 (2C=O); MS (m/z, %): 501 (M?, 2); Anal. Calcd for C23H20Br2O3:
C, 54.79; H, 4.00 %. Found: C, 54.52; H, 3.89 %.
2-(4-Bromobenzoyl)-3-(2-bromophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6u)
White powder; yield: 0.476 g (95 %); m.p. 143–145 °C; IR (KBr) (mmax, cm-1):
1
1695 (C=O); HNMR (400 MHz, CDCl3): d = 1.17 (3H, s, CH3), 1.21 (3H, s,
CH3), 2.24, 2.31 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.50, 2.57 (AB
system, J = 16.0 Hz, 2H, CHAHBCO), 5.10 (1H, 2d, J = 4.8 Hz, CH), 5.81 (1H,
2d, J = 4.8 Hz, CH), 7.16 (1H, t, J = 8.0 Hz, CH), 7.21 (1H, d, J = 8.0 Hz, CH),
7.33 (1H, t, J = 8.0 Hz, CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.58 (1H, d,
J = 8.0 Hz, CH), 7.84 (2H, d, J = 8.8 Hz, 2CH) ppm; 13C NMR (100 MHz,
CDCl3): d = 28.54 (CH3), 29.12 (CH3), 34.37 (C), 37.78 (CH2), 47.68 (CH), 51.10
(CH2CO), 90.19 (CH), 114.52 (C), 123.78 (C), 127.11 (C), 128.12 (CH), 129.12
(CH), 129.26 (2CH), 130.47 (2CH), 132.07 (C), 133.42 (CH), 140.03 (C), 140.72
(C), 176.26 (C), 190.93, 193.36 (2C=O); MS (m/z, %): 501 (M?, 4); Anal. Calcd for
C23H20Br2O3: C, 54.79; H, 4.00 %. Found: C, 54.91; H, 4.25 %.
2-(4-Bromobenzoyl)-3-(2-fluorophenyl)-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (6w)
White powder; yield: 0.398 g (90 %); m.p. 187 °C, IR (KBr) (mmax, cm-1): 1696
1
(C=O); HNMR (400 MHz, CDCl3): d = 1.18 (3H, s, CH3), 1.19 (3H, s, CH3),
2.22, 2.29 (AB system, J = 16.0 Hz, 2H, CHAHBC(CH3)2), 2.52, 2.59 (AB system,
J = 16.0 Hz, 2H, CHAHBCO), 4.75 (1H, d, J = 4.8 Hz, CH), 5.87 (1H, d,
J = 4.8 Hz, CH), 7.09 (1H, t, J = 9.2 Hz, CH), 7.16 (1H, t, J = 7.6 Hz, CH), 7.23
(1H, t, J = 7.6 Hz, CH), 7.30 (1H, m, CH), 7.46 (2H, d, J = 8.8 Hz, 2CH), 7.83
(2H, d, J = 8.8 Hz, 2CH) ppm; 13C NMR (100 MHz, CDCl3): d = 28.23 (CH3),
3
29.16 (CH3), 34.32 (C), 37.67 (CH2), 42.85 (d, JCF = 2.0 Hz, CH), 51.14
(CH2CO), 90.17 (CH), 113.41 (C), 116.08 (d, J = 21.0 Hz, Cortho), 124.70 (d,
J = 4.0 Hz, Cpara), 127.59 (d, J = 13.0 Hz, Cortho), 129.26 (2CH), 129.44 (d,
J = 8.0 Hz, Cmeta), 129.72 (d, J = 4.0 Hz, Cmeta), 130.39 (2CH), 131.80 (C),
140.79 (C), 160.64 (d, J = 246.0 Hz, Cipso), 176.39 (C), 191.45, 194.51 (2C=O);
MS (m/z, %): 442 (M?, 8); Anal. Calcd for C23H20BrFO3: C, 62.32; H, 4.55 %.
Found: C, 62.61; H, 4.67 %.
Results and discussion
In order to investigate the optimizing reaction conditions for the synthesis of highly
diastereoselective benzofuran derivatives, which are usable in a wide variety of
pharmacologically and biologically active compounds, we carried out the multi-
123

DABCO-catalyzed multi-component domino reactions for the…
component domino reaction between phenacyl bromide 1a (1 mmol), pyridine 2a
(1 mmol), benzaldehyde 4 (1 mmol) and 1,3-cyclohexanedione 5a (1 mmol) in
EtOH as a model. We initially, to minimize the formation of byproducts, first stirred
the phenacyl bromide and pyridine in EtOH for 2 min, and white solid was
observed. Next, benzaldehyde and 1,3-cyclohexanedione were added, and the
mixture was heated in EtOH under reflux. The desired product 6a was not obtained
when the reaction was carried out in ethanol for 8 h under reflux and catalyst-free
conditions (Table 1, entry 1). However, 6a was obtained in 42 % yield when the
reaction was conducted in the presence of piperidine (20 mol%) in ethanol (Table 1,
entry 2). Several bases were evaluated in the reaction as catalyst, including
piperidine, Et2NH, DMAP, DBU, and DABCO; these were all added in
substoechiometric amounts (20 mol%), and the reactions were carried out in
ethanol under reflux conditions. The catalytic efficiency of DABCO was the highest
(Table 1, entries 2–6). Different solvents were then appraised to determine the
impact of the solvent on the reaction yields. Water due to its strong hydrogen
bonding ability, hydrophobic effects and high polarity gave the best product yield
(Table 1, entries 6–11). We then evaluated the amount of catalyst required for this
transformation. An increase in the amount of DABCO more than 20 mol% showed
no remarkable improvement in the yield, whereas the yield was reduced by
decreasing the amount of DABCO to 10 mol% (Table 1, entries 11–13). Finally, the
Table 1 Optimization of reaction conditions of compound 6a
Entry
N-heterocycle
Cat (mol%)
Reaction conditions
Time (h)
Yield (%)a
1
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Isoquinoline
Quinoline
Acridine
N-methylimidazole
No catalyst
EtOH, reflux
EtOH, reflux
EtOH, reflux
EtOH, reflux
EtOH, reflux
EtOH, reflux
CH3CN, reflux
CHCl3, reflux
DMF, 100 °C
THF, reflux
H2O, reflux
H2O, reflux
H2O, reflux
H2O, rt
8
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
4
4
4
NR
42
2
Piperidine (20)
Et2NH (20)
3
67
4
DMAP (20)
DBU (20)
Trace
56
5
6
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (30)
DABCO (10)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
78
7
79
8
64
9
67
10
11
12
13
14
15
16
17
18
19
20
a
70
85
86
73
Trace
68
H2O, 60 °C
H2O, 80 °C
H2O, reflux
H2O, reflux
H2O, reflux
H2O, reflux
82
87
80
66
71
Isolated yields
123

S. Golchin et al.
reaction was performed at different temperatures to determine the optimum reaction
temperature. The reaction was conducted with 20 mol% DABCO in water at rt, 60,
80, and 100 °C, and the desired product 6a was formed in yields of 7, 68, 82, and
85 % (Table 1, entries 11 and 14–16), respectively.
We also applied a broad range of structurally diverse N-heterocycles to afford the
corresponding products that using isoquinoline led to a higher yield and shorter
reaction time in comparison with other N-heterocycles such as pyridine, quinoline,
acridine, and N-methylimidazole (Table 1, entries 11 and 17–20).
After extensive screening, we found that the optimized best yields and time
profiles were obtained with 20 mol% of DABCO in the presence of isoquinoline in
H2O under reflux conditions, which furnished the corresponding 2-benzoyl-3-
phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one 6a in 87 % yield within 2 h
(Table 1, entry 17).
Using these optimized conditions, we turned our attention to investigate the
scope and general applicability of this methodology by carrying out the synthesis of
benzofurans using phenacyl bromides, different aldehydes, and cyclic 1,3-
dicarbonyl compounds (Table 2).
As it is shown in Table 2, this domino reaction was efficiently promoted using
1,3-cyclohexanedione with reduced reaction times and increased yields rather than
dimedone and benzaldehydes with electron-withdrawing groups reacting rapidly
and giving higher yields, while substitutions of electron-rich groups on the benzene
ring required longer reaction times and got lower yields, and the reaction of
cinnamaldehyde also gave (E)-2-(4-chlorobenzoyl)-3-styryl-2,3,6,7-tetrahydroben-
zofuran-4(5H)-one 6f in 82 % yield (entry 6), whereas in the presence of aliphatic
aldehydes such as n-heptanal and n-octanal the product expected was not obtained
in this reaction conditions even after 8 h (entries 23, 24). Also, this catalytic system
was used for the synthesis of complex structures of bis-benzofuran derivatives from
the condensation reaction between phenacyl bromide (2 mmol), isoquinoline
(2 mmol), terphtalaldehyde (1 mmol), and 1,3-cyclohexanedione (2 mmol), but
the corresponding product was not obtained, and the product 6 g was formed.
The structures of these new compounds were deduced from their satisfactory
1
elemental and spectral (IR, H, 13C NMR and MS) studies. The mass spectra of
these compounds displayed molecular ion peaks at the appropriate m/z values.
In order to show the accessibility of the present work in comparison with only
one reported result in the literature, we summarized some of the results for the
preparation of 2-benzoyl-3-phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one in
Table 3. As shown in Table 3, this new catalytic system compared to previous
similar work has a number of advantages such as: shorter reaction time, higher
yields, and most importantly, avoidance of hazardous or toxic organic solvents.
The mechanism for this three-component domino reaction has been proposed in
Scheme 2 according to the literature [36]. The first step of this mechanism involves
the nucleophilic addition of isoquinoline 2c to the phenacyl bromide 1 and the
formation of the intermediate 3. On the basis of this mechanism, DABCO is an
effective catalyst for the formation of intermediate 7, which readily prepares in situ
from Knoevenagel condensation of aldehyde 4 with a 1,3-dicarbonyl compound 5.
In the presence of DABCO, intermediate 3 converts to its corresponding ylide form
123

DABCO-catalyzed multi-component domino reactions for the…
Table 2 Domino one-pot three-component synthesis of polyfunctionalized benzofuran derivatives by
using DABCO (20 mol%) as catalyst in the presence of isoquinoline in water under reflux
Entry Ar group
X
R
Product Time (h) Yield (%)a Melting point
m.p. (°C)/Lit.
m.p. (°C) [Ref]
1
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
2
1
1
1
3
3
3
2
2
2
4
3
1
1
1
2
4
3
3
2
2
2
8
8
87
95
91
89
84
82
87
89
85
89
84
89
95
85
89
95
81
81
89
89
95
90
–
127–129/128–130 [36]
199–202/this work
162–164/this work
156–158/this work
173–175/this work
151–154/this work
206/this work
2
4-NO2 C6H4
4-F C6H4
Cl
Cl
Cl
Cl
Cl
Cl
3
4
4-CN C6H4
2-Thienyl
5
6
CH=CH C6H5
4-CHO C6H4
7
6g
6h
6i
8
4-NO2-3-Cl C6H4 Br
194–196/this work
171–172/this work
180–182/this work
147–149/this work
169–170/this work
207–210/this work
166–168/this work
183–185/this work
140–141/this work
155–157/this work
177–180/this work
159–161/this work
135–136/this work
143–145/this work
187/this work
9
2-F C6H4
Br
Br
Br
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
2-Br C6H4
4-OH C6H4
1-Naphthyl
4-NO2 C6H4
4-F C6H4
6j
6k
6l
Cl CH3 6m
Cl CH3 6n
Cl CH3 6o
Cl CH3 6p
Cl CH3 6q
Cl CH3 6r
Cl CH3 6s
Br CH3 6t
Br CH3 6u
Br CH3 6w
4-CN C6H4
2-Cl C6H4
4-OH C6H4
2-Thienyl
1-Naphthyl
4-Br C6H4
2-Br C6H4
2-F C6H4
n-Heptanal
n-Octanal
Cl
Cl
H
H
–
–
–
–
–
Isolated yields
Table 3 Comparison the results of DABCO with Et3N in the synthesis 2-benzoyl-3-phenyl-2,3,6,7-
tetrahydrobenzofuran-4(5H)-one
Entry
Cat (mol%)
Conditions
Time (h)
Yield (%)a
References
1
2
a
Et3N
CH3CN, reflux
H2O, reflux
12
2
66
87
[36]
DABCO
This work
Isolated yields
8, to be able to react (Michael addition) easily with intermediate 3 and to eventually
give rise to the formation of intermediate 9. Finally, the carbanion transfers to
resonance-stabilized enolate through the keto-enol tautomerism, which in turn
substitutes isoquinoline (intramolecular SN2) to produce the final product benzo-
furan 6.
123

S. Golchin et al.
Scheme 2 Proposed mechanism for the synthesis of benzofuran derivatives
Conclusions
In conclusion, we have developed a procedure for the facile synthesis of various
potentially biologically active polyfunctionalized benzofurans, using one-pot three-
component domino reactions. This strategy provides a rapid and efficient
methodology for the preparation of benzofurans in excellent chemo-, regio- and
stereoselectivities. This protocol has the advantages of convenient one-pot
operation, short reaction times, high isolated yields of the pure products, easy
work-up and avoidance of hazardous or toxic catalysts and organic solvents.
Furthermore, it can be considered as environmentally friendly, since it requires the
use of neither organic solvent nor metal-containing catalysts.
Acknowledgments We gratefully acknowledge financial support from the Research Council of the
Islamic Azad University of Yazd.
References
1. J. Yu, F. Shi, L.Z. Gong, Acc. Chem. Res. 44, 1156 (2011)
2. M.S. Singh, G.C. Nandi, T. Chanda, RSC Adv. 3, 14183 (2013)
3. Z. Xu, M. Ayaz, A.A. Cappelli, C. Hulme, ACS Comb. Sci. 14, 460 (2012)
4. A.S. Pereteanu, T.J.J. Muller, Org. Biomol. Chem. 11, 5127 (2013)
5. Q. Gao, P. Zhou, F. Liu, W.J. Hao, C. Yao, B. Jiang, S.J. Tu, Chem. Commun. 51, 9519 (2015)
6. Q. Gao, W.J. Hao, F. Liu, S.J. Tu, S.L. Wang, G. Li, B. Jiang, Chem. Commun. 52, 900 (2016)
7. R. Mohebat, A. Yazdani Elah Abadi, M.T. Maghsoodlou, M. Mohammadi, Res. Chem. Intermed. 42,
5915 (2016)
8. R. Mohebat, A. Yazdani Elah Abadi, M.T. Maghsoodlou, Res. Chem. Intermed. 42, 6039 (2016)
9. M. Li, H. Cao, Y. Wang, X.L. Lv, L.R. Wen, Org. Lett. 14, 3470 (2012)
10. J.M. Khurana, A. Chaudhary, A. Lumb, B. Nand, Green Chem. 14, 2321 (2012)
123

DABCO-catalyzed multi-component domino reactions for the…
11. J. McNulty, P. Das, Eur. J. Org. Chem. 24, 4031 (2009)
12. J. McNulty, P. Das, Tetrahedron Lett. 50, 5737 (2009)
13. J. McNulty, P. Das, D. McLeod, Chem. Eur. J. 16, 6756 (2010)
14. S. Narayan, J. Muldoon, M.G. Finn, V.V. Fokin, H.C. Kolb, K.B. Sharpless, Angew. Chem. Int. Ed.
21, 3157 (2005)
15. P. Das, D. McLeod, J. McNulty, Tetrahedron Lett. 52, 199 (2011)
16. M. Smith, J. March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure
(Wiley, Hoboken, 2007)
17. R. Breslow, A fiftty-year perspective on chemistry in Organic Reactions in Water, ed. by
M. Lindstrom (Blackwell, Oxford, 2007), pp. 1–28
18. R. Breslow, D.C. Rideout, J. Am. Chem. Soc. 102, 7816 (1980)
19. R. Breslow, Acc. Chem. Res. 24, 159 (1991)
20. G.D. McCallion, Curr. Org. Chem. 3, 67 (1999)
21. W.S. Sheen, I.L. Tsai, C.M. Teng, I.S. Chen, Phytochemistry 36, 213 (1994)
22. M. Takasugi, S. Nagao, T. Masamune, A. Shirata, K. Takahashi, Tetrahedron Lett. 19, 797 (1978)
23. K.M. Zareba, Drugs Today 42, 75 (2006)
24. G.A. Kraus, I. Kim, Org. Lett. 5, 1191 (2003)
25. A.A. Deana, G.E. Stokker, E.M. Schultz, R.L. Smith, E.J. Cragoe, H.F. Russo, L.S. Watson, J. Med.
Chem. 26, 580 (1983)
26. E. Wenkert, B.L. Buckwalter, J. Am. Chem. Soc. 94, 4367 (1972)
27. F.R. Petronijevic, P. Wipf, J. Am. Chem. Soc. 133, 7704 (2011)
28. J. Boonsompat, A. Padwa, J. Org. Chem. 76, 2753 (2011)
29. S. Kiren, X. Hong, C.A. Leverett, A. Padwa, Org. Lett. 11, 1233 (2009)
30. K.C. Nicolaou, P.S. Baran, Y.L. Zhong, K.C. Fong, H.S. Choi, J. Am. Chem. Soc. 124, 2190 (2002)
31. M. Anary-Abbasinejad, N. Shams, M. Heidari, ARKIVOC ix, 13 (2012)
32. M.H. Mosslemin, N. Shams, H. Esteghamat, H. Anaraki-Ardakani, Chin. Chem. Lett. 24, 1095
(2013)
33. M. Anary-Abbasinejad, H.D. Farashah, A. Hassanabadi, H. Anaraki-Ardakani, N. Shams, Synth.
Commun. 42, 1877 (2012)
34. H. Anaraki-Ardakani, M.H. Mosslemin, M. Anary-Abbasinejad, S.H. Mirhosseini, N. Shams,
ARKIVOC xi, 343 (2010)
35. M. Anary-Abbasinejada, N. Shams, A. Hassanabadi, Phosphorus. Sulfur Silicon Relat. Elem. 185,
1823 (2010)
36. Q.F. Wang, H. Hou, L. Hui, ChG Yan, J. Org. Chem. 74, 7403 (2009)
123