Imidazolium ylide mediated tandem Knoevenagel–Michael–O-cyclization sequence for the synthesis of multi-substituted 4,5-dihydrofurans

Article abstract of DOI:10.1080/00397911.2020.1821226

The stereoselective syntheses of novel trans-5-aroyl-2,4-diaryl-4,5-dihydrofuran-3-carbonitriles have been achieved via a one-pot, three-component tandem protocol involving aroyl acetonitriles, aromatic aldehydes, and imidazolium ylide in the presence of

Full text of DOI:10.1080/00397911.2020.1821226

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Imidazolium ylide mediated tandem
Knoevenagel–Michael–O-cyclization sequence
for the synthesis of multi-substituted 4,5-
dihydrofurans
Sivakumar Sathiyamoorthi , Abdulrahman I. Almansour , Suresh Kumar
Raju , Arumugam Natarajan & Raju Ranjith Kumar
To cite this article: Sivakumar Sathiyamoorthi , Abdulrahman I. Almansour , Suresh Kumar
Raju , Arumugam Natarajan & Raju Ranjith Kumar (2020): Imidazolium ylide mediated tandem
Knoevenagel–Michael–O-cyclization sequence for the synthesis of multi-substituted 4,5-
dihydrofurans, Synthetic Communications, DOI: 10.1080/00397911.2020.1821226
To link to this article: https://doi.org/10.1080/00397911.2020.1821226
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https://doi.org/10.1080/00397911.2020.1821226
Imidazolium ylide mediated tandem
Knoevenagel–Michael–O-cyclization sequence for the
synthesis of multi-substituted 4,5-dihydrofurans
a
b
b
Sivakumar Sathiyamoorthi , Abdulrahman I. Almansour , Suresh Kumar Raju ,
b
a
Arumugam Natarajan , and Raju Ranjith Kumar
a
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, India;
Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
b
ABSTRACT
ARTICLE HISTORY
The stereoselective syntheses of novel trans-5-aroyl-2,4-diaryl-4,5-
dihydrofuran-3-carbonitriles have been achieved via a one-pot,
three-component tandem protocol involving aroyl acetonitriles, aro-
Received 5 August 2020
KEYWORDS
matic aldehydes, and imidazolium ylide in the presence of Et N.
3
Aroylacetonitrile; 45-
dihydrofuran; imidazolium
ylide; Knoevenagel reaction;
tandem reaction
GRAPHICAL ABSTRACT
Introduction
Furan derivatives are important class of heterocycles ubiquitous in natural products and
[
1–3]
synthetic compounds.
Furans are constituents of a number of biologically active
[
3]
[4]
compounds and are also valuable intermediates in organic syntheses. For example,
the nitrofurans are significant drugs used as antibiotics and antimicrobials (Fig. 1).
Ranitidine is used to treat peptic ulcer and gastroesophageal reflux diseases whereas
heliconol A, bullatenone, and evodone display antifungal and antibacterial activities.
[
5]
[
6]
[
7]
The biological significances of furan derivatives have attracted the interest of synthetic
chemists en route to discover efficient methodologies for the synthesis of hybrid hetero-
[
8]
cycles comprising furan core. After the first synthesis of furan by Limprich in 1870,
[
9]
several methods have been reported. Among the various methods available, the pyri-
[
10]
dinium ylide-assisted syntheses of furans have gained considerable attention.
It offers
a facile and efficient access to diverse furan derivatives. Pyridinium ylides was first
[
11]
reported by Kr o€ hnke
in 1935 and since then these ylides have been widely investi-
[
12]
gated as they react with various electrophiles to form variety of hybrid heterocycles.
CONTACT Raju Ranjith Kumar
raju.ranjithkumar@gmail.com
Department of Organic Chemistry, School of
Chemistry, Madurai Kamaraj University, Madurai, Tami Nadu, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
S. SATHIYAMOORTHI ET AL.
Figure 1. Selected drugs with furan nucleus.
Nevertheless, the use of pyridine has generated some limitations due to toxicity. On the
other hand, the imidazolium salts are relatively low toxic and serve as the best alternate
[
13]
for pyridinium ylides.
The imidazolium salts have been used as precursors of stable carbenes
[
14]
and as ionic
apart from serving as efficient ligands for the prepar-
[
15]
liquids for organic syntheses
ation of various transition metal complexes possessing biological activities
[
16]
and as
Moreover, imidazolium salts have received less atten-
[
17]
efficient fluorescence materials.
tion in synthetic organic chemistry. In this work, we envisaged to synthesize novel,
highly substituted dihydrofuran derivatives through a one-pot three-component tandem
strategy involving 1-methyl-3-(2-oxo-2-phenylethyl)-1H-imidazol-3-ium bromides, aroyl
acetonitriles and aromatic aldehydes. This work also stems from our continuous effort
[
18]
in synthesizing hybrid heterocycles through tandem/domino reactions.
To the best of
our knowledge, this is the first report for the synthesis of furans utilizing imidazo-
lium salt.
Results and discussion
Initially, in order to determine the optimum conditions for this one pot transformation,
the reaction of benzoyl acetonitrile 1, 4-chlorobenzaldehyde 2i and imidazolium salt 3,
presumably affording 5-benzoyl-4-(4-chlorophenyl)-2-phenyl-4,5-dihydro-furan-3-car-
bonitrile 4i was investigated. Organic bases such as L-proline, piperidine, pyrrolidine,
DABCO, DBU, and Et N (1 equiv. in each case) were screened in refluxing ethanol
3
(
Table 1). From the observations, Et N was found to be the ideal base, wherein the
3
reaction completed in 3 h resulting quantitative yield of the product 4i (97%).
Furthermore, after completion of the reaction, the product 4i precipitated in the reac-
tion vessel and was isolated just by filtration (Table 1, entry 6). Other bases employed
in the reaction resulted in comparatively lesser yield of 4i and the product needed to be
isolated after column chromatography. In the presence of L-proline (Table 1, entry 1),
the reaction failed to afford the product 4i but a light yellow precipitate was formed
after 4 h, which was found to be the Knoevenagel intermediate 5i (Scheme 1). However,
the reaction of 5i with 3 in the presence of L-proline failed to afford the product 4i
(Scheme 1). The reaction afforded lesser yield of 4i when carried out in solvents like
acetonitrile, methanol, and tetrahydrofuran (Table 1, entries 7–9). Hence, ethanol was
the ideal solvent for this reaction.

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SYNTHETIC COMMUNICATIONS
3
Table 1. Optimization of reaction conditions.
a
Entry
Base
L-Proline
Piperidine
Pyrrolidine
DBU
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Time (h)
Yield (%)
b
1
2
3
4
5
6
7
8
9
a
8
9
8
10
10
3
4
6
9
–
23
27
45
36
97
85
70
40
DABCO
Et
Et
Et
Et
3
N
3
N
3
N
3
N
CH
3
CN
MeOH
THF
b
Isolated yield; Expected product not formed.
Scheme 1. Reaction of intermediate 5i and 3.
1
The structure of dihyrofuran 4i was elucidated with the help of ESI-mass, FT-IR, H,
1
3
C and 2D NMR spectroscopy. The ESI-mass of 4i had a characteristic molecular ion
þ
peak at 385.89 (M ). The IR spectrum of 4i showed strong absorptions at 1691 and
ꢀ
1
1
2
197 cm due to the carbonyl and nitrile groups, respectively. In the H NMR spec-
trum of 4i, the two doublets at 4.78 and 5.85 ppm (J¼ 5.7 Hz) were assigned to H-4
and H-5, respectively. The distinct assignment of these chemical shifts arises from the
fact that H-4 showed HMBC with the nitrile carbon whereas H-5 did not. Further, H-4
showed (i) C,H-COSY correlation with carbon signal at 51.8 ppm due to C-4 and (ii)
HMBC with carbon signals at 84.8, 89.3, 129.2, 137.8, 166.5, and 192.2 ppm, which were
0
0
00
assigned to C-3, C-5, C-2 , C-1 , C-2 and C¼O, respectively. Further, H-5 showed
C,H-COSY correlation with carbon signal at 89.3 ppm due to C-5 and HMBC with car-
bon signals at 51.8, 84.8, 137.8, and 166.5 ppm, which can be assigned to C-4, C-3, C-
0
0
1
13
1
and C-2, respectively. The H and C chemical shifts and selected HMBC of 4i are
given in the supplementary data (Fig. S39).
A plausible mechanism for the formation of 4i is given in Scheme 2. Initially, the imidazo-
0
lium salt 3 in the presence of base forms imidazolium ylide 3 in situ. The simultaneous
Knoevenagel condensation of benzoyl acetonitrile 1 and 4-chlorobenzaldehyde 2i affords
0
the intermediate 5i. Subsequently, the ylide 3 upon Michael addition with the
a,b-unsaturated ketone 5i affords the intermediate 6, which undergoes an intramolecular O-
cyclization to afford the final product 4i with the removal of N-methylimidazole.

4
S. SATHIYAMOORTHI ET AL.
Scheme 2. Proposed mechanism for the formation 4i.
Scheme 3. Synthesis of tetra-substituted dihydrofurans 4.
Table 2. Library of dihydrofurans 4a–s.
a
Entry
Comp
R
X
Y
Yield (%)
[
19]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
H
H
H
H
H
2-Cl
H
96 (92)
92
94
91
94 [
94 (92)
92
4-MeO
H
4-MeO
4-F
2-Cl
2-Me
3-Br
3-Br
4-Br
4-Cl
19]
H
4-MeO
4-MeO
H
92
97
1
1
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
8
9
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
H
H
4-Cl
4-Cl
4-Me
4-Me
4-Cl
4-Cl
3-Cl
4-Cl
4-F
4-MeO
4-MeO
4-MeO
H
4-MeO
4-Cl
4-F
H
4-Cl
4-MeO
94
94
93
90
91
93
93
95
4-Me
4-Me
4-Me
4-MeO
4-MeO
2-Me
2-Me
4-F
93
94
4s
Quantitative yields obtained, except for the loss during workup.

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5
Figure 2. ORTEP diagrams of 4b and 4l.
With the optimal condition, viz. Et N–EtOH base–solvent pair in hand and the struc-
3
ture of 4i established, the synthesis of a library of dihydrofuran-3-carbonitriles 4 was
performed by varying aroyl acetonitriles 1, aromatic aldehydes 2, and imidazolium
ylides 3 (Scheme 3). The imidazolium salts 3 were prepared following literature proce-
[
10
dure. f] All the reactions occurred smoothly under the optimized condition with the
available variations. A total of nineteen novel dihyrofuran derivatives 4a–s were synthe-
sized in quantitative yields (Table 2).
The structure of all the dihydrofurans 4a–s was elucidated unambiguously with the
help of NMR spectroscopy and in the cases of 4b and 4l, the structure was further con-
[
20]
firmed from single-crystal X-ray studies.
The ORTEP diagram (Fig. 2) revealed that
H-4 and H-5 are trans.
Conclusions
This work reports the one-pot three-component tandem reactions for the expedient syn-
thesis of 5-aroyl-2,4-diphenyl-4,5-dihydrofuran-3-carbonitriles 4 in quantitative yields.
This reaction proceeded via a tandem Knoevenegal condensation–Michael addition–O-
cyclization process and resulted in the formation of three new bonds (two C–C and one
C–O) in a single synthetic operation.
Experimental section
General procedure for the synthesis of dihydrofurans 4
A mixture of aroyl acetonitrile 1 (1.0 mmol), aromatic aldehyde 2 (1.0 mmol), and imi-
dazolium salt 3 (1.0 mmol) was dissolved in EtOH (10 mL). Then Et N (1.0 mmol) was
3
added and the mixture refluxed on a water bath. The progress of the reaction was
monitored by TLC. After 3 h the reaction mixture was cooled and the precipitated solid
was filtered and washed with cold ethanol and dried under vacuum to obtain pure 4.
5
-Benzoyl-4-(4-chlorophenyl)-2-phenyl-4,5-dihydrofuran-3-carbonitrile 4i Yellow
ꢁ
1
solid; Yield 97%; mp 185 C; H NMR (300 MHz, CDCl ) d : 4.78 (d, 1H, J ¼ 5.7 Hz,
3
H
Ar-CH), 5.85 (d, 1H, J ¼ 5.7 Hz, Ar-CH), 7.30 (d, 2H, J ¼ 8.4 Hz), 7.41 (d, 2H, J

6
S. SATHIYAMOORTHI ET AL.
¼
8.4 Hz), 7.41–7.54 (m, 5H), 7.66 (t, 1H, J ¼ 7.5 Hz), 7.94 (d, 2H, J ¼ 7.8 Hz), 8.03 (d,
1
3
2
1
H, J ¼ 7.8 Hz); C NMR (75 MHz, CDCl ) d : 51.8, 84.8, 89.3, 116.0, 127.0, 127.4,
3
C
28.8, 128.9, 129.0, 129.2, 129.6, 132.0, 133.5, 134.4, 134.5, 137.7, 166.5, 192.2; Anal.
Calcd for C H ClNO : C, 74.71; H, 4.18; N, 3.63%. Found C, 74.60; H, 4.10; N, 3.74%.
2
4
16
2
1
13
Full experimental detail, H and C NMR spectra. This material can be found via
the “Supplementary Content” section of this article’s webpage.
Acknowledgments
The authors would like to thank the Department of Science and Technology, New Delhi for
funds under IRHPA program for the high-resolution NMR facility in the Department.
Funding
The project was supported by Researchers Supporting Project number RSP-2020/231, King Saud
University, Riyadh, Saudi Arabia.
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3