Synthesis of 2-(4-amino substituted benzylidene) indanone analogues from aromatic nucleophilic substitution (SNAr) reaction

Article abstract of DOI:10.1080/00397911.2018.1492726

A novel, efficient and convenient procedure has been developed for the synthesis of 2-(4-amino-substituted benzylidene)indanone derivatives. In the first step, the reaction of 4-fluorobenzaldehyde with 5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one in the pre

Full text of DOI:10.1080/00397911.2018.1492726

Synthetic Communications
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Synthesis of 2-(4-amino substituted benzylidene)
indanone analogues from aromatic nucleophilic
substitution (SNAr) reaction
Keshvar Rahimpour, Roghaye Nikbakht, Alireza Aghaiepour & Reza Teimuri-
Mofrad
To cite this article: Keshvar Rahimpour, Roghaye Nikbakht, Alireza Aghaiepour & Reza
Teimuri-Mofrad (2018): Synthesis of 2-(4-amino substituted benzylidene) indanone analogues
from aromatic nucleophilic substitution (SNAr) reaction, Synthetic Communications, DOI:
10.1080/00397911.2018.1492726
To link to this article: https://doi.org/10.1080/00397911.2018.1492726
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https://doi.org/10.1080/00397911.2018.1492726
Synthesis of 2-(4-amino substituted benzylidene) indanone
analogues from aromatic nucleophilic substitution
(SNAr) reaction
Keshvar Rahimpour, Roghaye Nikbakht, Alireza Aghaiepour, and
Reza Teimuri-Mofrad
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran
ABSTRACT
ARTICLE HISTORY
Received 19 May 2018
A novel, efficient and convenient procedure has been developed for
the synthesis of 2-(4-amino-substituted benzylidene)indanone deriva-
tives. In the first step, the reaction of 4-fluorobenzaldehyde with 5,
6-dimethoxy-2, 3-dihydro-1H-inden-1-one in the presence of NaOH in
EtOH was described. In the next step, a variety of aliphatic and aro-
matic amines were reacted with 2-(4-fluorobenzylidene)-5, 6-dime-
thoxy-2, 3-dihydro-1H-Inden-1-one via aromatic substitution (SNAr)
reaction to produce 2-(4-aminobenzylidene)-5, 6-dimethoxy-2, 3-dihy-
dro-1H-Inden-1-one derivatives as a novel class of 1-indanones.
These products have been successfully prepared in good to excellent
yields. 1 H and 13 C NMR, FT-IR spectroscopy and CHN analysis sup-
ported the proposed structures of the products.
KEYWORDS
Alzheimer’s disease;
donepezil; indanone;
nucleophilic aromatic
substitution (SNAr)
GRAPHICAL ABSTRACT
CONTACT Reza Teimuri-Mofrad
teymouri@tabrizu.ac.ir
Department of Organic and Biochemistry, Faculty of
Chemistry, University of Tabriz, Tabriz 51664, Iran.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
K. RAHIMPOUR ET AL.
Introduction
1-Indanones are the important synthetic intermediates for agrochemical and pharma-
ceutical compounds as well as for olefin polymerization.[1] The indanone nucleus as a
biologically active group is present in the structure of many drugs and biomaterials.[2]
Synthetic indanone-based derivatives are known to have various pharmacological activ-
ities such as: diuretic, hypoglycemic, antihypertensive, antiproliferative, antimicrobial,
acetylcholinesterase inhibitors, and in the treatment of Alzheimer’s disease (AD) like
donepezil hydrochloride (Aricept); for example, has a 1-indanone core.[3]
It is known that acetylcholinesterase (AChE) inhibitors are the first and the most
developed group of drugs approved for AD treatment; tacrine, donepezil, and rivastig-
mine are well-known inhibitors.[4] Donepezil exhibits excellent effects in the early-to-
moderate stages of AD patients. The benzylpiperidine and 5,6-dimethoxyindanone
moieties of donepezil interact with the peripheral and central binding site of AChE sep-
arately.[5,6] There are various routes to synthesize donepezil in the literature, but these
procedures have certain disadvantages, such as expensive catalysts, multiple reduction
steps, side products, and low yields.[7,8] Due to these disadvantages, development of
novel, simple, and efficient routes for the synthesis of donepezil and donepezil-like ana-
logs continues to attract a great deal of interest for scientists.[9–11]
These observations encouraged us to design and synthesize new donepezil analogs via
a SNAr reaction (Fig. 1), in which the 5,6-dimethoxy-2,3-dihydro-1H-inden-1-one ring
was retained as the main core and new side-chains with various amine groups were sub-
stituted at the para position of the benzylidene group. In our previous report,[12] we
demonstrated that this class of compounds could be prepared using an N-arylation reac-
tion catalyzed by CuI. In this work, we decided to examine the SNAr reaction for the
synthesis of these types of donepezil analogs.
Results and discussion
Aryl-nitrogen bonds are prevalent in many compounds with pharmaceutical and bio-
logical interest. The development of synthetic methods to form these bonds has been
widely studied. The aromatic nucleophilic substitution has been a powerful method for
introducing an amine group in place of a halogen atom in some aryl halides, particu-
larly fluorides. Therefore, as a starting point, we synthesized 2-(4-halobenzylidene)-5, 6-
dimethoxy-2, 3-dihydro-1H-inden-1-one according to the procedure optimized in refer-
ence[12] as our main starting materials (Scheme 1). We know that the SNAr reaction is a
Figure 1. Structure of donepezil (I) and our suggested compounds (II).

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Scheme 1. Synthesis of 2-(4-aminobenzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one.
Table 1. Various used conditions in the SNAr reaction.
Entry
X
Solvent
Base
Catalyst
Temp (oC)
Yield (%)
1
2
3
4
5
6
7
8
F
F
F
F
F
F
F
F
F
F
F
Cl
Br
Toluene
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
K2CO3
K3PO4
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
–
–
–
–
–
–
–
80
80
80
80
80
100
80
80
80
16
47
58
48
65
68
60
18
75
81
87
53
23
9
HDTMAB
HDTMAB
HDTMAB
HDTMAB
HDTMAB
10
11
12
13
90
100
100
100
transition metal-free carbon-heteroatom bond formation. In general, the SNAr reaction
requires harsh conditions, a suitable base to enhance the nucleophilicity and an activat-
ing group such as a nitro and cyano substituent on the aryl halide to stabilize the SNAr
Meisenheimer complex.[13] In our compounds, the conjugation of the double bond with
the carbonyl group withdraws electron density in the aromatic ring. C2 and C4 are
highly electrophilic sites. Thus, a C4 halide can be displaced by a nucleophile in an add-
ition-elimination SNAr process.
As a model compound, we optimized the SNAr reaction feasibility of the 2-(4-halo-
benzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one (3a-c) with imidazole (4a) as
shown in Table 1. The aromatic nucleophilic substitution was studied using a variety of
solvents, bases, and ligands at different temperatures. The results show that among vari-
ous solvents and bases screened at 80 ꢀC, the best result was obtained when DMF and
K2CO3 were used as a solvent and the base, respectively (Table 1, entry 5). It was also
observed that hexadecyltrimethylammonium bromide (HDTMAB) facilitated the SNAr
reaction of 3a and (to some extent) 3 b,[12] allowing N-arylation without added CuI in
good yield (Table 1, entry 9).
The reaction was studied at different temperatures and 100 ꢀC was selected as the
optimal temperature (Table 1, entry 11). Thus, a catalyst system consisting of

4
K. RAHIMPOUR ET AL.
Figure 2. Addition- elimination mechanism of SNAr reaction with 2-(4-fluorobenzylidene)-5, 6-dime-
thoxy-2, 3-dihydro-1H-inden-1-one.
Figure 3. Aliphatic and aromatic used amines.
HDTMAB, and K2CO3 in DMF at 100 ꢀC was employed for further studies. As
expected, comparing the results of using different halobenzaldehydes (Table 1, entries
11–13), shows that yield of fluoro derivative (3c) is much higher than that of the corre-
sponding bromo and chloro analogs for the SNAr reaction. While fluoride is the worst
leaving group for the SN2 reaction, it is the best for the SNAr reaction due to its small
size (does not impede approach of the nucleophile) and electronegativity (imparts par-
tial positive charge) to the carbon. Based on these facts, the fluorine atom could acceler-
ate the first step in the addition-elimination mechanism (Figure 2).
To explore the scope and generality of this optimized condition, we extended this
method to the synthesis of the corresponding indanone derivatives (5) via the SNAr
reaction between the 2-(4-fluorobenzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-
one and a variety of aliphatic and aromatic amines (Fig. 3).
As shown in Figure 4, the reactions were carried out efficiently and the desired prod-
ucts were produced in good yields (79–87%). The availability of 4-fluorobenzaldehyde
as a starting material, the use of inexpensive reagents, and higher total yields of final
products are some advantages of this method over previous reports.

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5
Figure 4. Final synthesized compounds (5a–5g).
Experimental
Solvents and reagents were purchased from Merck, Fluka, Sigma, Aldrich, and Yantai
Suny Chem. International Co., Ltd. Commercially solid reagents were used without fur-
ther purification. Column chromatography was performed on silica gel 60 (Merck, grain
1
size 63–200 lm). All reactions were carried out under an atmosphere of argon. The H
NMR spectra were recorded using a Bruker FT-400 MHz spectrometer at room tem-
perature, 13 C NMR spectra were determined on the same instrument at 100 MHz and
with CDCl3 as a solvent while chemical shifts are presented in delta values expressed in
ppm referenced to CHCl3 residue at 7.25 and 78 ppm. The FT-IR spectra were recorded
on a Bruker–Tensor 270 spectrophotometer as KBr disks or as thin films between salt
plates. Melting points were determined on a MEL-TEMP model 1202 D apparatus and
are uncorrected.
General procedure for the synthesis of compound (3)
To a stirred solution of 4-halobenzaldehyde (1 mmol) and indanone (1 mmol) in EtOH
(10 mL), an aqueous solution of NaOH (10%) was added dropwise. The reaction mix-
ture was stirred overnight at room temperature. The obtained solid was collected by fil-
tration and purified by recrystallization from EtOH to give desired product as a
pure solid.
2-(4-Fluorobenzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one (3c)
Pale yellow solid; Yield 85%; mp: 198–200 ꢀC; 1 H NMR (400 MHz, CDCl3): d (ppm)
7.63–7.65 (2 H, d, J ¼ 8.6 Hz, Ar–H), 7.61(1 H, s, methine–H), 7.13–7.15 (2 H, d,
J ¼ 8.6 Hz, Ar–H), 7.11(1 H, s, Ar–H), 6.97 (1 H, s, Ar–H), 3.99 (3 H, s, O–CH3), 3.94
(3 H, s, O–CH3), 3.93 (2 H, s, –inden–CH2); FT-IR (KBr): 2958, 1691, 1591, 1490, 1302,
1224, 1085 cmꢁ1
.

6
K. RAHIMPOUR ET AL.
General procedure for the synthesis of compounds (5)
To a solution of 3c (2 mmol), amine (4 mmol) in DMF (3 mL), K2CO3 (4 mmol), and
HDTMAB (0.001 mmol) were added and the reaction mixture was heated at 100 ꢀC for
24 h. When the reaction was complete (by TLC), the reaction mixture was cooled,
poured into water, and extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The residue was purified
by column chromatography (EtOAc/n-hexane, 2:8) to give the desired products.
2-(4-Imidazolobenzylidene)-5, 6-dimethoxy-2, 3-dihydro-1H-inden-1-one (5a)[12]
Yellow solid; Yield 87%; mp: 223–225 ꢀC; 1 H NMR (400 MHz, CDCl3): d (ppm)
7.91(1 H, s, methine–H), 7.71–7.73 (2 H, d, J ¼ 8.2 Hz, Ar–H), 7.55 (1 H, s, Ar–H),
7.44–7.46 (2 H, d, J ¼ 8.2 Hz, Ar–H), 7.32 (1 H, s, Ar–H), 7.31(1 H, s, Ar–H), 7.22 (1 H,
s, Ar–H), 6.96 (1 H, s, Ar–H), 3.98 (3 H, s, O–CH3), 3.93 (3 H, s, O–CH3), 3.92 (2 H, s,
indene–CH2); 13 C NMR (100 MHz, CDCl3): d (ppm) 191.7, 154.5, 148.7, 143.6, 136.4,
135.1, 134.3, 133.7, 130.8, 129.9, 129.8, 129.5, 126.0, 120.3, 116.7, 106.1, 104.0, 55.2,
55.1, 31.0; Anal. Calcd. For C21H18N2O3: C, 72.89; H, 5.25; N, 8.09; Found: C, 72.61; H,
5.27; N, 8.06%; FT-IR (KBr): 2935, 2838, 1688, 1635, 1497, 1303, 1250, 1093 cmꢁ1
.
Conclusion
In this study, an efficient and convenient method was described for the synthesis of 2-
(4-aminobenzylidene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-ones as drug scaffolds
(5a–g), starting from 4-fluorobenzaldehyde and 5,6-dimethoxy-2,3-dihydro-1H-indene-
1-one (2). Nucleophilic aromatic substitution of compound 3c with a variety of aliphatic
1
and aromatic amines resulted in the corresponding final products. H NMR, 13 C NMR,
FT-IR and CHN supported the assigned structures of the products. This method pro-
vides a convenient synthetic route to a variety of substituted indanone derivatives in
good yields.
Supporting information
Supplementary data (general experimental details, characterization data) copies of the
1
FT-IR, H NMR, 13C NMR and CHN analysis of all the synthesized donepezil analogues
associated with this article can be found, in the online version.
Funding
We thank the Research Affairs of the University of Tabriz for financial support.
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