Synthesis of a series of novel 2,3-dihydrofurano-γ-lactone derivatives using DABCO as catalyst in an aqueous medium

Article abstract of DOI:10.3184/174751917X15005654784030

A one-pot, green and efficient synthesis of twelve trans-2-(4-chlorobenzoyl)-3-aryl-3,6-dihydrofuro[3,4-b]furan-4-ones has been achieved via a three-component condensation of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide with furan-2,4-dione and an araldehyde in the presence of catalytic amounts of 1,4-diaza-bicyclo[2.2.2]octane (DABCO) in water under reflux conditions.

Full text of DOI:10.3184/174751917X15005654784030

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 AUGUST, 469–472
RESEARCH PAPER 469
Synthesis of a series of novel 2,3-dihydrofurano-γ-lactone derivatives using
DABCO as catalyst in an aqueous medium
Maryam Salaria, Mohammad H. Mosslemina*and Alireza Hassanabadib
aDepartment of Chemistry, Yazd Branch, Islamic Azad University, Yazd, Iran
bDepartment of Chemistry, Zahedan Branch, Islamic Azad University, Zahedan, Iran
A one-pot, green and efficient synthesis of twelve trans-2-(4-chlorobenzoyl)-3-aryl-3,6-dihydrofuro[3,4-b]furan-4-ones has been achieved
via a three-component condensation of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide with furan-2,4-dione and an araldehyde
in the presence of catalytic amounts of 1,4-diaza-bicyclo[2.2.2]octane (DABCO) in water under reflux conditions.
Keywords: 2,3-dihydrofurano-γ-lactone derivatives, aryl aldehydes, 4-chlorophenacyl bromide, furan-2,4-dione, DABCO, green chemistry
Multi-component reactions are useful and efficient methods in
organic synthesis. The major advantages of these reactions are
a single purification step, higher yields than stepwise assembly,
the use of simple and diverse precursors to construct complex
molecules and the use of only a single promoter or catalyst.
Thus, the development of new multi-component reactions is
a popular area of research in organic chemistry and from a
green chemistry point of view.1–3 Dihydrofurans are important
heterocycles commonly found in a large variety of naturally
occurring substances.4 The development of new and efficient
methods for their synthesis remains an area of current interest
and a whole series of new synthetic methods have appeared in
the literature.5–8 The synthesis of dihydrofurans was reported by
reaction of an aryl aldehyde, a cyclic 1,3-diketone, and 2-bromo-
1-phenylethanone or 4-nitrobenzyl bromide in pyridine in the
presence of 10 mol% sodium hydroxide in refluxing aqueous
solution.9 Recently, organic reactions in aqueous media have
attracted a great deal of attention10 as a result of increasing
interest in the concepts of sustainability and green chemistry.11
Also the latter synthesis used a procedure first described by
Wang et al.12 and Khan et al.9, in which they synthesised a
series of dihydrofurans via the pyridine-catalysed reaction of
phenacyl bromides with a series of aromatic aldehydes and
4-hydroxycoumarin in presence of catalytic amounts of NaOH
or Et3N. Although many of the reported methods are effective,
some of them suffer from disadvantages such as harsh reaction
conditions, use of hazardous solvents, long reaction times,
complex work-ups and purification procedures, high catalyst
loadings and moderate yields. Therefore, the development of a
simple, mild and efficient method is still needed. In the present
work, we used 1,4-diaza-bicyclo[2.2.2]octane (DABCO) as an
efficient catalyst to overcome these limitations.
DABCO has received considerable attention as an inexpensive,
eco-friendly, highly reactive, easy to handle and non-toxic
basic catalyst13 for various organic transformations, affording
the corresponding products in excellent yields with high
selectivity. The reactions are environmentally friendly and the
catalyst can be recycled in some cases.14 In continuation of our
previous work on the synthesis of heterocyclic compounds15,16
we decided to investigate the reaction of 2-[2-(4-chlorophenyl)-
2-oxoethyl)]isoquinolinium bromide 2 with furan-2,4-dione 3
and an aromatic aldehyde 4 in the presence of catalytic amounts
of DABCO in water under reflux conditions (Scheme 1).
Results and discussion
Using a previously reported method,17 we prepared in
nearly quantitative yield one of the starting materials,
2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide 2
by treatment of isoquinoline with 4-chlorophenacyl bromide 1
in acetonitrile (Scheme 2).
As
a
test run,
a
three-component reaction of
2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium
bromide
Cl
O
O
O
O
_
Br
O
N
N
H
3
+
O
N
H
+
O
H2O , Reflux , 3 h
2
Ar
5
Cl
Ar
H
O
4
O
Scheme 1
O
_
Br
Br
CH3CN, rt, 20 min
O
+
+
N
N
Cl
2
1
Cl
Scheme 2
* Correspondent. E-mail: mhmosslemin@iauyazd.ac.ir

470 JOURNAL OF CHEMICAL RESEARCH 2017
2 with furan-2,4-dione 3 and benzaldehyde 4 (Ar = Ph) in the
presence of catalytic amounts of DABCO in refluxing water
gave the expected product 5a (Ar = Ph) in an excellent yield of
92% (Table 1). Then 11 other araldehydes 4 (Ar = various) were
then employed to prepare the corresponding analogues 5b–l
(Ar = various) (Table 1).
Yields were uniformly high, 90–96%, for both electron-
donating and electron-withdrawing groups. The structures of
compounds 5a–l were deduced from their elemental analyses
and their IR, 1H NMR and 13C NMR spectra. The mass spectra
of compounds 5a–l were fairly similar and displayed molecular
ion peaks. In the H NMR spectra, the two protons at the
1
2,3-position of the dihydrofuran ring displayed two doublets at
4.32 and 6.08 ppm with a vicinal coupling constant J = 5.2 Hz. It
has been documented that in cis-2,3-dihydrofurans, the vicinal
coupling constant of the two methine protons is 7–10 Hz, while
in trans-2,3-dihydrofurans, the vicinal coupling constant is 2.8–
6.0 Hz. Therefore, we concluded that the thermodynamically
stable trans isomers of the 2,3-dihydrofuran derivatives were
formed.18
A proposed mechanism for this reaction is shown in Scheme
3. The formation of the product can be explained as follows. The
Table 1 Yields of a series of 2,3-dihydrofurano-γ-lactone derivatives
5
(Ar = various) prepared from 2-[2-(4-chlorophenyl)-2-oxoethyl)]
2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium bromide
2
isoquinolinium bromide 2, furan-2,4-dione 3 and an araldehyde 4 (Ar =
various) (Scheme 1)a
undergoes deprotonation in the presence of aqueous DABCO to
give the reactive isoquinolinium ylide 6. The furan-2,4-dione 3
reacts with aromatic aldehyde 4 in the presence of DABCO to give
the Knoevenagel product 7. Compound 7 reacts instantly with the
isoquinolinium ylide 6 to form the zwitterionic intermediate 8,
which undergoes cyclisation with the elimination of isoquinoline
to give 5.
In summary, here we report a simple and efficient one-
pot condensation of 2-[2-(4-chlorophenyl)-2-oxoethyl)]
isoquinolinium bromide with furan-2,4-dione and an aromatic
aldehyde in the presence of catalytic amounts of DABCO in
water under reflux conditions to yield 2,3-dihydrofurano-γ-
lactone derivatives. The advantages of this method are simply
available starting materials, short reaction times, easy and clean
work-up and excellent yields.
Product Ar
Yield (%)b
92
93
95
90
92
94
88
96
91
92
90
93
M.p. (°C)
142–144
143–145
148–150
168–170
171–173
140–142
165–167
174–176
177–179
167–169
170–172
163–165
5a
5b
5c
5d
5e
5f
C6H5
2-O2NC6H4
4-O2NC6H4
2-ClC6H4
4-ClC6H4
2-FC6H4
5g
5h
5i
5j
5k
5l
4-CH3OC6H4
4-FC6H4
4-Cl-3-O2NC6H3
4-NCC6H4
4-CH3C6H4
4-BrC6H4
aReaction conditions: DABCO (15 mol%) was added to
a
stirred mixture of
Experimental
2-[2-(4-chlorophenyl)-2oxoethyl)]isoquinolinium bromide 2 (1 mmol), furan-2,4-dione 3
(1 mmol) and an araldehyde 4 (Ar = various) (1 mmol) in water (10 mL) and the mixture
heated at reflux for 3 h.
bYields refer to the pure isolated products.
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyser. Mass spectra were recorded on a FINNIGAN-MAT
_
Br
+
N
_
Br
N
H
O
+
N
+
N
N
O
2
+
Cl
N
6
_
Ar
Cl
O
4
O
O
DABCO
O
+
_
O
H2O
Ar
O
O
H
7
3
O
+
N
_
+
O
N
_
6
N
Cl
Ar
Ar
5
_
O
O
O
O
O
O
Cl
8
7
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2017 471
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-400 MHz spectrometer
(1H NMR at 400 Hz, 13C NMR at 100 Hz) in CDCl3 using TMS as an
internal standard. Chemical shifts (δ) are given in ppm and coupling
constants (J) are given in Hz. 2-[2-(4-Chlorophenyl)-2-oxoethyl)]
isoquinolinium bromide 2 was prepared by a literature method.17
Others chemicals used in this work were purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
129.3, 132.3, 138.7, 160.2, 170.8, 174.4, 186.4; MS m/z (%): 358 (5).
Anal. calcd for C19H12ClFO4: C, 63.61; H, 3.37; found: C, 63.75; H,
3.50%.
Trans-2- (4 - chlorobenzoyl) -3- (4 -methox yphenyl) -3,6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5g): White powder; m.p.
165–167 °C; IR (KBr) (νmax cm−1): 2924, 2843, 1728, 1694, 1642,
1617, 1514, 1418, 1258, 1210, 1235, 1176, 1080, 1022, 935; 1H NMR: δ
3.81(s, 3H, OCH3), 4.34 (d, J = 4.8 Hz, 1H), 4.92 (s, 2H, OCH2), 6.09
(d, J = 4.8 Hz, 1H), 6.85–8.05 (m, 8H, arom); 13C NMR: δ 38.6, 55.4,
66.2, 84.8, 99.1, 114.2, 128.6, 128.8, 130.2, 132.3, 132.9, 138.7, 157.6,
170.2, 174.7, 186.5; MS m/z (%): 370 (7). Anal. calcd for C20H15ClO5:
C, 64.79; H, 4.08; found: C, 64.95; H, 4.21%.
Synthesis of 2,3-dihydrofurano-γ-lactone derivatives; general
procedure
DABCO (15 mol %) in H2O (5 mL) was added to a magnetically
stirred solution of 2-[2-(4-chlorophenyl)-2-oxoethyl)]isoquinolinium
bromide (1 mmol), furan-2,4-dione (1 mmol) and an aryl aldehyde
(1 mmol) in H2O (10 mL). The mixture was then refluxed for 3 h. The
progress of the reaction was monitored by TLC. After cooling to r.t.,
the solid product was filtered and recrystallised from ethanol to afford
the pure products 5a–l.
Trans-2-(4-chlorobenzoyl)-3-phenyl-3,6-dihydrofuro[3,4-b]furan-
4(2H)-one (5a): White powder; m.p. 142–144 °C; IR (KBr) (νmax
cm−1): 2924, 2853, 1718, 1645, 1448, 1406, 1035, 754, 575; 1H NMR:
δ 4.32 (d, J = 5.2 Hz, 1H, CH), 4.82 (s, 2H, CH2), 6.08 (d, J = 5.2 Hz,
1H, CH), 7.27–8.04 (m, 9H, arom); 13C NMR: δ 38.5, 66.3, 84.7, 99.1,
1258, 127.8, 128.7, 130.2, 132.4, 138.5, 140.6, 168.2, 174.6, 188.3; MS
m/z (%): 340 (5). Anal. calcd for C19H13ClO4: C, 66.97; H, 3.85; found:
C, 67.12; H, 3.72%.
Tr a ns-2- (4 - ch loro b e n zoyl) -3 - (4 - f lu orop h e nyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5h): White powder, m.p.
174–176 °C; IR (KBr) (νmax cm−1): 2923, 2836, 1724, 1646, 1412, 1024,
754, 534; 1H NMR: δ 4.24 (d, J = 5.0 Hz, CH, 1H), 4.86 (s, 2H, OCH2),
6.10 (d, J = 5.0 Hz, CH, 1H,), 7.16–8.06 (m, 8H, arom); 13C NMR: δ
39.2, 66.3, 84.6, 99.1, 115.4, 128.6, 129.8, 130.2, 132.3, 136.2, 138.7,
160.4, 170.9, 175.8, 187.7; MS m/z (%): 358 (3). Anal. calcd for
C19H12ClFO4: C, 63.61; H, 3.37; found: C, 63.78; H, 3.52%.
Trans-2-(4-chlorobenzoyl)-3-(4-chloro-3-nitrophenyl)-3,6-
dihydrofuro[3,4-b]furan-4(2H)-one (5i): White powder; m.p.
176–178 °C; IR (KBr) (νmax cm−1): 2932, 2854, 1727, 1647, 1524,
1
1410, 747, 578; H NMR: δ 4.40 (d, J = 4.8 Hz, CH, 1H,), 4.89 (s,
2H, OCH2), 6.12 (d, J = 4.8 Hz CH, 1H), 7.59–8.32 (m, 7H, arom);
13C NMR: δ 37.5, 66.7, 84.3, 99.4, 125.1, 125.6, 128.6, 130.2, 132.3,
132.8, 135.2, 138.7, 139.6, 147.5, 170.2, 174.6, 186.8; MS m/z (%): 419
(6). Anal. calcd for C19H11Cl2NO6: C, 54.31; H, 2.64; N, 3.33; found: C,
54.45; H, 2.80; N, 3.47%.
Trans-2-(4-chlorobenzoyl)-4-oxo-2,3,4,6-tetrahydrofuro[3,4-b]
furan-3-yl)benzonitrile (5j): White powder; m.p. 167–169 °C; IR
(KBr) (νmax cm−1): 2935, 2854, 1725, 1645, 1526, 1412, 747, 575;
1H NMR: δ 4.35 (d, J = 4.8 Hz, CH, 1H), 4.94 (s, 2H, OCH2), 6.08
(d, J = 4.8 Hz, CH, 1H), 7.60–8.07 (m, 8H, arom); 13C NMR: δ 38.7,
66.3, 84.8, 99.2, 109.8, 119.2, 128.6, 128.7, 130.2, 132.1, 132.3, 138.7,
144.6, 170.2, 174.6, 186.3; MS m/z (%): 365 (5). Anal. calcd for
C20H12ClNO4: C, 65.67; H, 3.31; N, 3.83; found: C, 65.84; H, 3.46; N,
3.70%.
Tra ns-2- (4 - chlorobenzoyl) -3 - (4 - m ethylph enyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5k): White powder; m.p.
170–172 °C; IR (KBr) (νmax cm−1): 2932, 2864, 1726, 1647, 1453, 1406,
1025, 753; 1H NMR: δ 2.18 (s, 3H, CH3), 4.44 (d, J = 5.4 Hz, CH, 1H),
4.84 (s, 2H, OCH2), 6.05 (d, J = 5.4 Hz, CH, 1H), 7.02–8.05 (m, 8H,
arom); 13C NMR: δ 21.3, 38.4, 66.4, 84.8, 99.1, 127.6, 1287, 128.9,
130.2, 132.4, 135.6, 137.6, 138.7, 170.1, 174.6, 186.2; MS m/z (%): 354
(7). Anal. calcd for C20H15ClO4: C, 67.71; H, 4.26; found: C, 67.88; H,
4.40%.
Tr a ns-2- (4 - c h l oro b e n zoyl) -3 - (4 - bro m o p h e nyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5l): White powder; m.p.
163–165 °C; IR (KBr) (νmax cm−1): 2915, 2821, 1718, 1646, 1405, 1028,
754, 538; 1H NMR: δ 4.22 (d, J = 5.2 Hz, CH, 1H), 4.88 (s, 2H, OCH2),
6.32 (d, J = 5.2 Hz, CH, 1H), 7.32–8.02 (m, 8H, arom); 13C NMR: δ
39.2, 66.3, 84.6, 99.1, 120.3, 128.6, 129.8, 130.2, 131.5, 132.3, 138.7,
139.6, 170.8, 174.4, 186.4; MS m/z (%): 419 (8). Anal. calcd for
C19H12BrClO4: C, 54.38; H, 2.88; found: C, 54.52; H, 3.02%.
Tr a n s - 2 - ( 4 - c h l o r o b e n z o y l ) - 3 - ( 2 - n i t r o p h e n y l ) - 3 , 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5b): White powder; m.p.
143–145 °C; IR (KBr) (νmax cm−1): 2924, 2839, 1728, 1644, 1512, 1415,
1
1026, 745, 570; H NMR: δ 4.56 (d, J = 5.1 Hz, CH, 1H,), 4.85 (s,
CH2, OCH2), 6.12 (d, J = 5.1 Hz CH, 1H), 7.71–8.07 (m, 8H, arom);
13C NMR: δ 33.9, 66.3, 83.8, 99.1, 124.3, 126.8, 128.3, 128.6, 130.2,
132.3, 134.4, 138.7, 148.2, 170.8, 174.4, 186.4; MS m/z (%): 485 (8).
Anal. calcd for C19H12ClNO6: C, 59.16; H, 3.14; N, 3.63; found: C,
59.28; H, 3.29; N, 3.80%.
Tr a n s - 2 - ( 4 - c h l o r o b e n z o y l ) - 3 - ( 4 - n i t r o p h e n y l ) - 3 , 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5c): White powder; m.p.
148–150 °C; IR (KBr) (νmax cm−1): 2933, 2856, 1726, 1642, 1523,
1
1413, 747, 575; H NMR: δ 4.36 (d, J = 4.8 Hz, CH, 1H), 4.92 (s,
CH2, OCH2), 6.08 (d, J = 4.8 Hz, CH, 1H), 7.58–8.42 (m, 8H, arom);
13C NMR: δ 38.7, 66.3, 84.6, 99.1, 123.8, 128.6, 130.2, 132.3, 138.7,
145.1, 146.7, 170.8, 174.4, 186.4; MS m/z (%): 385 (6). Anal. calcd for
C19H12ClNO6: C, 59.16; H, 3.14; N, 3.63; found: C, 59.30; H, 3.32; N,
3.77%.
Tra ns-2- (4 - ch lorobe nzoyl) -3 - ( 2- ch loroph e nyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5d): White powder; m.p.
168–170 °C; IR (KBr) (νmax cm−1): 2924, 2843, 1725, 1644, 1450,
1402, 1027, 754, 575; 1H NMR: δ 4.32 (d, J = 5.2 Hz, CH, 1H), 4.75 (s,
CH2, OCH2), 5.98 (d, J = 5.2 Hz, CH, 1H), 7.16–8.06 (m, 8H, arom);
13C NMR: δ 33.4, 66.1, 84.5, 99.1, 126.6, 127.3, 128.8, 129.1, 130.2,
132.3, 133.1, 138.2, 138.6, 170.5, 174.6, 186.3; MS m/z (%): 374 (9).
Anal. calcd for C19H12Cl2O4: C, 60.82; H, 3.22; found: C, 70.00; H,
3.39%.
Tra ns-2- (4 - ch lorobe nzoyl) -3 - (4 - ch loroph e nyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5e): White powder; m.p.
171–173 °C; IR (KBr) (νmax cm−1): 2934, 2826, 1723, 1646, 1414,
Received 21 June 2017; accepted 7 July 2017
Paper 1704844
https://doi.org/10.3184/174751917X15005654784030
Published online: 31 July 2017
1
1024, 758, 536; H NMR: δ 3.91 (d, J = 5.2 Hz, CH, 1H), 4.92 (s,
CH2, OCH2), 6.52 (d, J = 5.2 Hz, CH, 1H), 7.30–8.02 (m, 8H, arom);
13C NMR: δ 38.6, 66.4, 84.4, 99.1, 128.7, 129.1, 130.2, 131.5, 132.3,
138.7, 139.6, 170.8, 174.4, 186.4; MS m/z (%): 374 (7). Anal. calcd for
C19H12Cl2O4: C, 60.82; H, 3.22; found: C, 60.97; H, 3.35%.
References
Tr a n s-2- (4 - ch l oro b e n zoyl) -3 - ( 2- f l u oro p h e nyl) -3, 6 -
dihydrofuro[3,4-b]furan-4(2H)-one (5f): White powder; m.p.
140–142 °C; IR (KBr) (νmax cm−1): 2930, 2855, 1714, 1644, 1452,
1
2
3
A. Domling and I. Ugi, Angew. Chem., 2000, 112, 3300.
D.J. Ramon and M. Yus, Angew. Chem., 2005, 117, 1628.
A. Ulaczyk-Lesankom and D.G. Hall, Curr. Opin. Chem. Biol., 2005, 9,
266.
1
1402, 1026, 755, 574; H NMR: δ 4.34 (d, J = 5.2 Hz, CH, 1H), 4.92
(s, CH2, OCH2), 6.10 (d, J = 5.2 Hz, CH, 1H), 7.07–8.10 (m, 8H, arom);
13C NMR: δ 31.7, 66.1, 84.5, 99.1, 115.3, 124.2, 127.2, 127.5, 128.7,
4
5
B.H. Lipshutz, Chem. Rev., 1986, 86, 795.
G. Bar, A.F. Parson and C.B. Thomas, Tetrahedron Lett., 2000, 41, 7751.

472 JOURNAL OF CHEMICAL RESEARCH 2017
6
7
8
9
P. Müller, Y.F. Allenbach and G. Bernardinelli, Helv. Chim. Acta, 2003, 86,
3164.
H. Hagiwara, K. Sato, T. Suzuki and M. Ando, Tetrahedron Lett., 1997, 38,
2103.
W. Cao, W. Ding, J. Chen, Y. Chen, Q. Zang and G. Chen, Synth. Commun.,
2004, 34, 1599.
A.T. Khan, M.S. Lal and R. Basha, Synthesis, 2013, 45, 406.
12 Q.F. Wang, H. Hou, L. Hui and C.G. Yan, J. Org. Chem., 2009, 74, 7403.
13 H. Yang, R. Tian and Y. Li, Front. Chem. Chin., 2008, 3, 279.
14 B. Baghernejad, Eur. J. Chem., 2010, 1, 54.
15 M. Salari, M.H. Mosslemin and A. Hassanabadi, J. Chem. Res., 2017, 41,
60.
16 M. Salari, A. Hassanabadi and M.H. Mosslemin, J. Chem. Res., 2017, 41,
271.
17 M. Anary-Abbasinejad, K. Charkhati and A. Hassanabadi, J. Chem. Res.,
2009, 2, 95.
10 C.-J. Li and T.-H. Chan, Organic reactions in aqueous media. Wiley. New York,
1997.
11 C. Jiménez-González and D.J.C. Constable, Green chemistry and engineering:
a practical design approach. Wiley, Hoboken, 2011.
18 A.T. Khan, M.S. Lal and R. Basha, Synthesis, 2013, 45, 406.