Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel isoindolinone derivatives

Article abstract of DOI:10.1007/s00706-020-02661-y

Abstract: An efficient and green microwave method has been developed for the synthesis of novel isoindolinone derivatives with good yields. The framework of these derivatives was constructed from β-ketocarboxylic acids, various primary amines, and 2-carboxybenzaldehyde via cetrimonium bromide salt-promoted multicomponent cascade of decarboxylation/lactamization reaction. This methodology features a simple, environmentally friendly approach, employing water as a green solvent and using a one-pot, three-component reaction. The synthesized compounds were evaluated for their antimicrobial activity in vitro against six microorganisms, namely Escherichia coli, Serratia, Staphylococcus aureus, Bacillus subtilis, Aspergillus niger, and Fusarium oxysporum. The results revealed that these derivatives have a significant antimicrobial activity. In addition, the drug-likeness of these derivatives has been evaluated. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-020-02661-y

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02661-y
ORIGINAL PAPER
Microwave‑assisted green synthesis, antimicrobial activity,
and drug‑likeness of novel isoindolinone derivatives
Ahmed Majeed Jassem1 · Adil Muala Dhumad1
Received: 24 April 2020 / Accepted: 3 July 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
An efcient and green microwave method has been developed for the synthesis of novel isoindolinone derivatives with
good yields. The framework of these derivatives was constructed from β-ketocarboxylic acids, various primary amines, and
2-carboxybenzaldehyde via cetrimonium bromide salt-promoted multicomponent cascade of decarboxylation/lactamization
reaction. This methodology features a simple, environmentally friendly approach, employing water as a green solvent and
using a one-pot, three-component reaction. The synthesized compounds were evaluated for their antimicrobial activity in vitro
against six microorganisms, namely Escherichia coli, Serratia, Staphylococcus aureus, Bacillus subtilis, Aspergillus niger,
and Fusarium oxysporum. The results revealed that these derivatives have a signifcant antimicrobial activity. In addition,
the drug-likeness of these derivatives has been evaluated.
Graphic abstract
Keywords Microwave-assisted synthesis · Green solvent · Cetrimonium bromide · Isoindolinone derivatives ·
Antimicrobial activity
Introduction
activities [5, 6]. Zopiclone (C) is found to be clinically use-
ful in the treatment of sedative efects [7] and compound
D exhibited an inhibitory potency toward aldose reductase
[8]. Furthermore, compound E appears to be an important
agent to evaluate the potential therapeutic of ELOVL6 and
ELOVL3 inhibitors [9] (Fig. 1).
Isoindolinone skeleton is an important privileged class in
exhibiting a broad range of potent therapeutic and pharma-
cological activities [1, 2]. The isoindolinone moiety is found
in natural products and biologically active compounds [3, 4].
Examples of biological activities of isoindolinone deriva-
tives include therapeutic agents such as pagoclone (A) and
pazinaclone (B) which showed anxiolytic and hypnotics
Several methodologies for the synthesis of isoindolinone
derivatives have been reported in the literature, including
Mukaiyama/Mannich lactamization [10], Ugi/Diels–Alder
reaction [11], Sonogashira coupling, followed by ring clo-
sure and redox reactions [12] and cascade reactions [13,
14]. Reportedly, in some methods various catalysts have
been explored in the synthesis of isoindolinone deriva-
tives such as camphorsulfonic acid ( )-CSA [15], DBU
[16], bis(triphenylphosphine)palladium(II) dichloride [17],
rhodium(III) [18], l-proline [19], Ru(II) [20], and In(OTf)3
[21]. Nevertheless, the reported methodologies generally
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02661-y) contains
supplementary material, which is available to authorized users.
* Ahmed Majeed Jassem
ahmedmajeedhsskia@gmail.com
1
Department of Chemistry, College of Education for Pure
Sciences, University of Basrah, Basrah, Iraq
Vol.:(0123456789)
1 3

A. M. Jassem, A. M. Dhumad
O
N
Cl
H
O
N
N
N
N
O
O
O
N
N
O
O
N
N
Cl
N
N
O
O
Cl
(A)
Pazinclone (B)
Zopiclone (C)
e
Pagoclon
O
O
O
N
HN
CF
3
N
Cl
O
N
O
NH
O
(D)
(E)
Fig. 1 Some pharmacologically active isoindolinone derivatives
involve several drawbacks such as use of expensive catalysts,
many reagents, long reaction times, harsh reaction condi-
tions, multi-step strategy, and using toxic organic solvents
[12]. Thus, the development of efcient and green meth-
odologies for the synthesis of isoindolinone derivatives is
highly needed.
been extensively applied in the feld of organic synthesis, espe-
cially in multicomponent reactions (MCRs) [29]. MCRs ofer
an important synthetic methodology over linear methodology
due to their simplicity and unique ability to generate high
structural complexity with minimum synthetic steps [30, 31].
In continuation of our work to adopt the advantages of MW
irradiation and multicomponent reactions, we herein aim to
use MW irradiation, cetrimonium bromide (cetyltrimethylam-
monium bromide, CTAB) as a cheap catalyst and water as a
green solvent for the synthesis of novel isoindolinone deriva-
tives 4a–4j in a one-pot reaction. The isoindolinone deriva-
tives 4a–4j have been screened for their antimicrobial activity
as a continuation of our research toward antimicrobial lead
construction and the drug-likeness of these derivatives has
been evaluated.
In this context, the scope of green chemistry has been
receiving a huge attention in medicinal and organic chem-
istry [22]. One of the key principles of green chemistry is
avoiding the toxic solvents in chemical reactions or replacing
hazardous solvents with environmentally friendly solvents.
Water is a non-toxic and non-fammable solvent compared
with common organic solvents. The use of water as a green
solvent in the synthesis of isoindolinones has been under-
taken as a high level of chemical research [23].
Also, green chemistry has encouraged the use of green syn-
thetic methods. One method to address this target includes
using microwave (MW) irradiation technique [24]. The advan-
tages of using MW irradiation comprise an environmentally
eco-friendly approach [25], promotion of solvent-free reac-
tions [26], increase in product yields, reduction of reaction
times, enabling a concise control of the reaction conditions
[27], and minimizing side-products [28]. MW irradiation has
Results and discussion
Chemistry
β-Ketocarboxylic acids are efciently used to provide ketone
enolate via decarboxylation process. The ketone enolate
1 3

Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel…
reacts with many electrophilic partners and used in a vari-
ety of decarboxylative transformations. The model reaction
was selected from the reaction of 3-oxobutanoic acid (1a,
2.5 mmol), ammonium hydroxide (2a, 32%, 6 mmol), and
2-carboxybenzaldehyde (3, 1 mmol) in order to synthesize
isoindolinone derivative 4a. The reaction did not proceed
in the absence of catalyst as shown in Table 1 (entries 1 and
2). To our knowledge, the decarboxylation/lactamization
reaction by using CTAB as a quaternary ammonium salt is
unprecedented. The use of CTAB is found to be a signifcant
catalyst for an activation of decarboxylation reaction in the
presence of water as non-toxic solvent with only CO2 gener-
ated as non-hazardous waste. To evaluate the efciency of
CTAB compared to the reported catalysts, the model reac-
tion was tested in some of these catalysts including ( ) CSA,
l-proline, and DBU (Table 1, entries 3–7). Notably, an ef-
cient activity of catalyst (CTAB) was noted and the desired
product 4a was obtained in higher yield in water. Thus, the
efective concentration of CTAB was investigated for the
model reaction in water as a solvent. Firstly, at the catalytic
concentration of CTAB (20 mol%), the model reaction was
carried out at 20 min and aforded the desired product 4a
70% in yield (Table 1, entry 8). By increasing the reaction
time from 20 min to 30 min, the highest yield of the desired
product 4a was obtained (Table 1, entry 9). Increasing the
catalyst loading from 20 to 40 mol%, no a signifcant yield
was obtained at the same reaction time (30 min) (Table 1,
entry 10). As a result, 20 mol% of CTAB, water as a solvent,
and reaction time 30 min were chosen as the most appropri-
ate microwave conditions for the synthesis of novel isoin-
dolinone derivatives 4a–4j (Scheme 1).
The further extension of the present methodology was
focused on using various primary amines such as tryptamine
(2b), 2-phenylethanamine (2c), 4-(4-methoxyphenoxy)ani-
line (2d), 2-aminopyrimidine (2e), 4-(1H-imidazol-1-yl)-
aniline (2f), 4-aminoquinaldine (2g), and 2-aminobenzothia-
zole (2h) under optimized conditions. We speculated that the
multicomponent cascade of decarboxylation/lactamization
reaction was delicately infuenced by the electronic nature
of the substituted amines. Notably, diferent yields of the
corresponding isoindolinone derivatives varied with difer-
ent amines. In the presence of ammonium hydroxide and
aryl-alkylamines 2b, 2c, the reaction yields were consider-
ably increased, afording the corresponding isoindolinones
75–85% yields. The result also revealed that aromatic amines
with electron-donating substituents such as a methoxy group
aforded high yields than non-substituent aromatic amines.
Our postulated mechanism for the formation of isoin-
dolinone derivatives 4a–4j has been tentatively pro-
posed (Scheme 2). First of all, β-ketocarboxylic acid was
Table 1 The optimized conditions for the synthesis of isoindolinone derivative 4a
O
O
O
O
Different
conditions
NH
OH
H
OH
1a
O
O
NH
2a
3
3
4a
Entry
Method
Catalysis
Solvent
Temp/°C
Time
Yield/%a
1
2
3
4
5
6
7
8
9
10
Batch
Batch
Batch
MW
MW
MW
MW
MW
MW
MW
None
None
( )-CSA (20/mol%)
( )-CSA (20/mol%)
l-proline (20/mol%)
DBU (20/mol%)
MeOH
MeOH
DMSO
DMSO
MeOH
DMSO
DMSO
Water
r.t.
Refux
Refux
100, 75 P
100, 75 P
100, 75 P
100, 75 P
100, 75 P
100, 75 P
100, 75 P
24/h
10/h
8/h
30/min
30/min
30/min
30/min
20/min
30/min
30/min
–
–
35
32
35
42
50
70
80
65
DBU (40/mol%)
CTAB (20/mol%)
CTAB (20/mol%)
CTAB (40/mol%)
Water
Water
Bold values indicate the best microwave conditions for the synthesis of novel isoindolinone derivatives
aIsolated as a pure product
1 3

A. M. Jassem, A. M. Dhumad
Scheme 1
O
O
O
O
O
H2O, CTAB (20 mol%)
N
R
OH
H
X
OH
°
75 P, 100 C, 30 min
1a,
1b,
X = H
X = Ph
P = Power
O
X
R
NH
2
3
4a-4j
2a-2h
4a,
4b,
X = H, R = H
X = H, R =
2a,
2b,
R = H
R =
NH
4c,
4d,
X = Ph, R = H
X = Ph, R =
NH
NH
2c,
2d,
R =
R =
4e,
4f,
X = Ph, R =
X = Ph, R =
O
O
O
O
N
N
N
2e,
2f,
R =
4g,
4h,
X = Ph, R =
N
N
N
N
R =
N
X = Ph, R =
2g, R =
2h,
4i,
4j,
X = Ph, R =
X = Ph, R =
N
S
N
S
R =
deprotonated by amine in the presence of ammonium salt
(CTAB) to form dianion (an intermediate I) via the elec-
trostatic interaction which forms between the lone pair of
the substrate (two oxygen atoms) and the ammonium cation
[32]. The further condensation between the intermediate I
and 2-carboxybenzaldehyde gives an intermediate II (lac-
tone) which subsequently undergoes a decarboxylative addi-
tion and further ring-closing reaction. On the basis of the
proposed mechanism of lactone aminolysis (lactone ring-
opening) in the literature [33], this mechanism involves three
sequential chemical transformations. Initially, the carbonyl
group of lactone II is aminolyzed by an extra addition of
primary amine, forming the corresponding hydroxyamide
IV via a zwitterionic intermediate III. The formation of the
zwitterionic aminolysis intermediate III is rapid inference
for the present lactone II. Then, an addition of proton to
the hydroxyamide IV afords ketoamide V. After that, the
N-alkylation of a primary amine with the ketoamide V via
“hydrogen autotransfer” gives the corresponding aminoam-
ide VII. Finally, the aminoamide VII undergoes intramo-
lecular transamidation to aford the desired product VIII.
Biological activity
The bacterial microorganisms species used in this work
included bacterial species: Gram-negative bacteria
(Escherichia coli and Serratia) and Gram-positive bacte-
ria (Staphylococcus aureus and Bacillus subtilis). These
microorganisms were collected from the culture collec-
tion of microbiology constitute (Molecular Biology Lab,
Government College University, Pakistan). Antibacterial
activity of the synthesized compounds 4a–4j was screened
in an in vitro assay against these types of bacterial strains.
The plates of assay were inoculated with the bacterial test
via an addition of 1 cm3 which contains diluted inoculums
(106–107 CFU/cm3) to the media after solidifcation. The
wells of these plates were made from the tested compounds
(0.1 mg) dissolved in 1 cm3 DMSO and poured into the
wells. The incubation of these plates was further carried out
at 37 °C for 48 h, thereafter the inhibitory zones were evalu-
ated by diameters [34]. For positive controls, norfoxacin and
spiramycin (0.1 mg/cm3) were used as standard antibacterial
drugs, while DMSO was employed as a negative control.
On the other hand, antifungal activity of the synthesized
compounds 4a–4j was screened against two pathogenic
fungi, namely Aspergillus niger and Fusarium oxysporum by
1 3

Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel…
Scheme 2
CH
3
CH
3
CH
CH
2
14
CH
2
2
14
2
+
O
CH
–
Aminolysis
Ring-opening
O
-C
2
N
Br
+
–
N
Br
–
–
-H O
O
O
2
O
O
+
3
O
NH
R
NH
R
X
OH
2
X
O
NH
R
2
O
I
X
O
II
OH
O
O H
N
O H
O H
+
R
H
Hydrogen
autotransfer
NH
N R
N R
–
O
+
R
OH
2
- H
O
-H O
2
O
O
O
X
III
X
IV
X
V
O H
O
O H
N R
N R
Transamidation
N R
+
R NH
+ H
N
R
2
NH
R
O
O
O
X
X
X
VI
VIII
VII
the poison plate method. These species of fungi were incu-
bated in potato dextrose agar medium (PDA) at 25 1 °C for
5 days to obtain a new mycelium assay for antifungal test.
These mycelia were cut approximately 0.5 cm from stock
medium. The mycelia were then picked up by a needle of a
sterilized inoculation and further inoculated in the plate of
PDA. The fnal concentration of the synthesized compounds
4a–4j was adjusted to 0.1 mg, dissolved in 1 cm3 DMSO and
added to the PDA (9 cm3) in the culture medium. Flucona-
zole (0.1 mg/cm3) was used as a standard antifungal drug
for each experiment. All experiments were carried out in
triplicate and the results were evaluated as zone of inhibi-
tion in mm.
Antibacterial activity
The antibacterial activity of the synthesized isoindolinone
derivatives 4a–4j was screened as mentioned in “Experimen-
tal” section. The results showed that most of isoindolinone
derivatives 4a–4j exhibited reasonable degrees of inhibi-
tion against the screened bacterial microorganisms. Table 2
shows that against Escherichia coli, Serratia, Staphylococ-
cus aureus, and Bacillus subtilis, compounds 4a–4d and 4h
showed the best results, in that the mean zones of inhibition
were equal to 16–21 mm. Against the same microorganisms,
compound 4g showed moderate activity, with an inhibitory
zone equal to 13–15 mm, followed by compounds 4j and
4f with mean zones of inhibition equal to 12–14 mm. The
other synthesized compounds 4e and 4i exhibited inactivity
against all strains of bacterial organisms.
1 3

A. M. Jassem, A. M. Dhumad
Table 2 Antimicrobial activity
expressed as zone of inhibition
in diameter (mm) of novel
Comp.
Antibacterial activity
Antifungal activity
E. coli
Serratia
S. aureus
B. subtilis
A. niger
F. oxysporum
isoindolinone derivatives 4a–4j
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
19
20
16
16
5
12
14
18
NA
13
20
19
NT
20
18
19
20
NA
12
13
20
NA
12
25
23
NT
18
21
19
21
NA
13
15
18
NA
14
22
21
NT
17
18
16
16
NA
13
13
18
NA
13
20
22
NT
19
20
18
16
18
22
16
17
NA
14
17
21
NA
14
14
18
NA
16
NT
NT
24
NA
13
NT
NT
22
NFX
SPI
FCN
The bold font shows that compounds demonstrate a good activity
NT not tested, NA no activity, NFX norfoxacin, SPI spiramycin, FCN fuconazole. The blank of each
experiment was performed with the same concentration of DMSO
Bickerton et al. [35]. The QED parameters were calculated
Antifungal activity
using the implementation of the QEDw (weighted QED)
algorithm which is available in the FAF-Drugs 4 online ser-
vice [36]. The QED methodology describes eight molecu-
lar properties combined with drug-likeness and considers a
score ranging from zero (all properties unfavorable) to one
(all properties favorable). The score distribution was calcu-
lated for isoindolinone derivatives 4a–4j (Fig. 2a), showing
a reasonable degree of drug-likeness since the median scores
of QEDw for these derivatives was 0.58. When the obtained
data for all isoindolinone derivatives 4a–4j are displayed as
a cumulative frequency plot (Fig. 2b), it seems that some
derivatives possess a QEDw score greater than 0.58, with a
median value for the score distribution of 0.61. Favorably,
compared to the score (median QEDw) of 0.63 introduced
for a set of 771 oral drugs in Bickerton’s original report [35].
The QEDw scores ranked structures were ordered as follows:
compound 4d (QEDw 0.621), compound 4b (QEDw 0.610),
compound 4h (QEDw 0.584), compound 4f (QEDw 0.581),
compound 4j (QEDw 0.563), compound 4g (QEDw 0.556),
compound 4i (QEDw 0.528), and compound 4c (QEDw
0.502).
The results obtained from the present test expressed a difer-
ent behavior of isoindolinone derivatives 4a–4j in the anti-
fungal test (Table 2). The antifungal activity of the screened
compounds showed that against Aspergillus niger and Fusar-
ium oxysporum, compounds 4a–4d and 4h exhibited best
results, with inhibitory zones equal to 16–22 mm. Against
Aspergillus niger, compounds 4g and 4j showed good
results, with mean zones of inhibition equal to 16–17 mm,
while compound 4f exhibited moderate activity against these
types of fungal microorganisms. Against Aspergillus niger
and Fusarium oxysporum, compounds 4e and 4i exhibited
inactivity against these types of fungal microorganisms.
Drug‑likeness
Drug-likeness is a considerable guideline for the beginning
stages of drug discovery. Encouraged by the above result,
this led to our focus on the adoption of drug-likeness pro-
tocol in order to investigate the substituent patterns of the
screening compounds. These substituent patterns may posi-
tively afect a number of molecular properties. Thus, our
research focused on an expedient synthesis of isoindolinone
derivatives as a means to access medicinally relevant deriva-
tives with their potential applications for extension of struc-
tural variation.
When isoindolinone derivatives 4a–4j were analyzed
using the drug-like flter of FAF-Drugs 4, 9/10 compounds
passed with the only exception being 4a (isoindolinone
structural alert). Moreover, 4/10 were expected to possess
a good aqueous solubility, and 7/10 given log P values
below 3. The value of log P distribution which calculated
by the XLOGP3 strategy [37] is shown in Fig. 3c (median
2.02, IQR 1.50–2.55). The preceding results refect the
value of selecting to focus on the substituent patterns on
amine, and the core-structure of these derivatives since
Given the initial supposition that isoindolinone deriva-
tives of general structure 4a–4j would have desirable proper-
ties from a standpoint of drug discovery, the isoindolinone
derivatives 4a–4j were evaluated using the quantitative
estimate of drug-likeness (QED) parameter reported by
1 3

Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel…
Fig. 2 The present isoindolinone derivatives 4a–4j display favorable
drug-like properties. a QEDw score distribution for isoindolinone
derivatives 4a–4j. b A cumulative distribution plot of QEDw scores
for isoindolinone derivatives 4a–4j. c Distribution of calculated log P
values for isoindolinone derivatives 4a–4j
the present protocol has shown that some derivatives are
being predicated to have a good aqueous solubility and
avoid presenting an excessive lipophilicity. Given their
favourable drug-likeness, it is interesting to observe that
some of these derivatives may have potential applications
in medicinal chemistry.
good yields. Cetrimonium bromide as quaternary ammo-
nium salt plays an important role in this environmentally
friendly decarboxylative lactamization/transformation. The
obtained isoindolinone derivatives showed a good antimi-
crobial activity against six types of microorganisms, namely
Escherichia coli, Serratia, Staphylococcus aureus, Bacillus
subtilis, Aspergillus niger, and Fusarium oxysporum. Drug-
likeness of these derivatives is evaluated by the quantitative
estimate of drug-likeness (QED) method. The result showed
that the most of these derivatives typically provide favorable
drug-likeness properties. Such derivatives would therefore
demonstrate to be a valuable extension to testing decks, and
fnd their wide applications in drug discovery programs.
Conclusion
In conclusion, we have proved a green, rapid, and highly ef-
cient one-pot reaction under microwave strategy for the syn-
thesis of novel isoindolinone derivatives through decarboxy-
lation/lactamization cascade reaction in water. This strategy
tolerates β-ketocarboxylic acids, various primary amines,
2-carboxybenzaldehyde, and cetrimonium bromide as a cata-
lyst to aford a wide variety of isoindolinone derivatives in
1 3

A. M. Jassem, A. M. Dhumad
and extracted with ethyl acetate (3×20 cm3). The combined
organic layers were dried over Na2SO4, fltered, and concen-
trated under reduced pressure. Purifcation was performed
by a fash chromatography (eluent petroleum ether/ethyl
acetate, 6:4) to aford the titled isoindolinone derivatives.
Experimental
Commercially available chemicals and solvents were ordered
from Sigma Aldrich. All microwave reactions were car-
ried out by using Smith Creator™ Optimiser EXP reactor
(Vials™). Routine detecting of all reaction was performed
by thin layer chromatography (TLC) with silica gel 60 UV
255 on plates pre-coated (Merck), and the spots were visu-
alized with an alkaline aqueous solution of potassium per-
manganate (KMnO4) or UV light. Flash column chroma-
tography was performed by using silica gel 60 Å (230–400
mesh, Merck). Majority of the synthesized compounds was
obtained in > 95% purity. Melting points were measured
with Gallenkamp melting point apparatus in capillary tubes.
Mass spectrometry was performed on a Micro Mass LCT
operating in Electrospray mode (ES) (Leicester, UK). Infra-
red (IR) spectra were recorded on a Perkin Elmer Paragon
100 FT-IR spectrophotometer (Perkin Elmer, Leicester, UK)
using KBr pellets in the range 4000–500 cm−1, and charac-
teristic peaks are expressed in cm−1. 1H and 13C NMR spec-
tra were run on Bruker AV-400 spectrometer at 400 MHz
(1H) and 100.5 MHz (13C) at room temperature (Leicester,
UK). Deuterated chloroform was used as the internal sol-
vent (1H NMR: CDCl3: δ = 7.26 ppm; 13C NMR: CDCl3:
δ=77.16 ppm). Chemical shifts are expressed in parts per
million (ppm) from tetramethylsilane (TMS) with the sol-
vent resonance as the internal standard. The abbreviated
pattern is used to express the multiplicities: s for singlet; d
for doublet; dd for doublet of doublets, t for triplet and m,
multiplet. The completed protons of decoupling J are evalu-
ated by Hz unite. HPLC analysis for the synthesized com-
pounds was performed by using Phenomenex lux cellulose-1
3 μm column (4.6 mm×250 mm), 20% IPA in hexane, over
25 min, UV detection at 228 nm.
3‑(2‑Oxopropyl)isoindolin‑1‑one (4a) Compound 4a was
obtained as a pale solid. Yield 0.13 g (80%); m.p.: 130–
131 °C. All the physical data were identical for those pre-
pared previously (Ref. [40] m.p.: 131–133 °C).
2‑[2‑(1H‑Indol‑3‑yl)ethyl]‑3‑(2‑oxopropyl)isoindolin‑1‑one
(4b, C21H20N2O2) Compound 4b was obtained as an orange
1
solid; yield 0.11 g (75%); m.p.: 101–102 °C; H NMR
(400 MHz, CDCl3): δ = 2.04 (s, 3H, CH3), 2.55 (dd, 1H,
J = 8.5, 2.1 Hz, CH), 2.84 (dd, 1H, J = 7.6, 3.1 Hz, CH),
3.17 (t, 2H, J = 7.3 Hz, CH2), 3.48 (dd, 1H, J = 13.9,
6.8 Hz, CH), 4.27 (dd, 1H, J = 7.3, 2.8 Hz, CH), 5.0 (dd,
1H, J=4.1, 2.1 Hz, CH), 7.67–7.07 (m, 6H, Ar–H), 7.71 (d,
1H, J=7.8 Hz, Ar–H), 7.86 (d, 1H, J=6.6 Hz, Ar–H), 8.06
(s, 1H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3): δ=29.7
(CH3), 30.4 (CH2), 41.1 (CH), 46.3 (CH2), 55.5 (CH2), 111.2
(Ar–CH), 112.9 (Ar–CH), 118.8 (Ar–CH), 119.6 (Ar–CH),
122.2 (Ar–CH), 122.5 (Ar–CH), 123.5 (Ar–CH), 127.3 (Ar–
C), 128.4 (Ar–CH), 131.6 (Ar–CH), 132.0 (Ar–C), 136.3
(Ar–C), 145.6 (Ar–C), 168.3 (C=O), 205.8 (C=O) ppm; IR
(KBr): ̄ꢀ =3468 (N–H), 3056 (Ar–CH), 2986 (C–H), 1713
(C=O), 1681 (Ar–C=C) cm−1; HRMS (ESI+): m/z calcd for
C21H20N2O2 ([M+H]+) 333.1604, found 333.1598.
3‑(2‑Oxo‑2‑phenylethyl)isoindolin‑1‑one (4c) Compound
4c was obtained as pale solid. Yield 0.11 g (75%); m.p.:
159–160 °C. All the physical data were identical for those
prepared previously (Ref. [10] m.p.: 148–149 °C, Ref. [41]
m.p.: 160–162 °C).
3-Oxobutanoic acid (1a) [38] and 3-oxo-3-phenylpropa-
noic acid (1b) [39] were prepared according to literature
methods.
2‑[2‑(1H‑Indol‑3‑yl)ethyl]‑3‑(2‑oxo‑2‑phenylethyl)isoindo‑
lin‑1‑one (4d, C26H22N2O2) Compound 4d was obtained as
a red solid; yield 0.11 g (77%); m.p.: 108–109 °C; 1H NMR
(400 MHz, CDCl3): δ=3.05–2.99 (m, 2H, CH2), 3.21 (dd,
1H, J = 12.1, 3.6 Hz, CH), 3.36 (dd, 1H, J= 12.8, 5.0 Hz,
CH), 3.57 (dd, 1H, J = 16.1, 6.5 Hz, CH), 4.22 (dd, 1H,
J = 16.3, 7.0 Hz, CH), 5.31 (dd, 1H, J= 7.4, 4.9 Hz, CH),
7.51–7.4 (m, 7H, Ar–H), 7.60 (t, 1H, J = 7.4 Hz, Ar–H),
7.69 (d, 1H, J=7.8 Hz, Ar–H), 7.90–7.78 (m, 4H, Ar–H),
8.10 (s, 1H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 24.2 (CH2), 29.7 (CH2), 41.9 (CH), 56.1 (CH2), 118.6
(Ar–CH), 119.4 (CH, Ar), 119.5 (Ar–CH), 121.2 (Ar–CH),
122.1 (Ar–CH), 122.3 (Ar–C), 122.8 (Ar–C), 123.5 (Ar–C),
127.4 (Ar–CH), 128.1 (Ar–C), 128.4 (Ar–CH), 128.7 (Ar–
C), 131.6 (Ar–CH), 132.1 (Ar–CH), 133.7 (Ar–C), 136.2
(Ar–C), 145.9 (Ar–C), 168.5 (C=O), 197.4 (C=O) ppm; IR
(KBr): ̄ꢀ =3050 (Ar–CH), 2915 (C–H), 1663 (C=O), 1616
Microwave synthesis of isoindolinone derivatives
All microwave reactions were carried out in a capped
(10 cm3) microwave-vessel (borosilicate glass vial sealed)
which was ftted in a microwave cavity. The pressure was
set at 17 bar (average of an efective pressure=4 bar) with
power 75 W. A mixture of β-ketocarboxylic acid 1a or 1b
(6.0 mmol), primary amine 2a–2h (6.0 mmol), and CTAB
(0.2 mmol, 20 mol%) in 3 cm3 water was stirred for 5 min.
To this mixture, 2-carboxybenzaldehyde (3, 1.0 mmol) was
added and subjected to microwave irradiation at 100 °C for
30 min. When the reaction was completed (as indicated by
TLC), the reaction vessel was cooled to room temperature
1 3

Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel…
(Ar–C=C) cm−1; HRMS (ESI+): m/z calcd for C26H22N2O2
([M+H]+) 395.1767, found 395.1754.
2‑[4‑(1H‑Imidazol‑1‑yl)phenyl]‑3‑(2‑oxo‑2‑phenylethyl)isoin‑
dolin‑1‑one (4 h, C25H19N3O2) Compound 4h was obtained
as a colorless solid; yield 0.11 g (77%); m.p.: 150–151 °C;
1H NMR (400 MHz, CDCl3): δ = 3.42 (dd, 1H, J = 17.6,
7.4 Hz, CH), 3.81 (dd, 1H, J=17.6, 6.7 Hz, CH), 6.20 (dd,
1H, J=6.6, 2.5 Hz, CH), 7.50 (s, 1H, C3N2H3), 7.53–7.49
(m, 4H, Ar–H), 7.67 (d, 1H, J=2.2 Hz, C3N2H3), 7.70–7.60
(m, 5H, Ar–H), 7.83 (d, 1H, J=2.4 Hz, C3N2H3), 7.99–7.94
(m, 4H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3): δ=26.8
(CH), 43.7 (CH2), 122.9 (C, C3N2H3), 124.8 (Ar–CH), 125.6
(Ar–C), 126.0 (Ar–CH), 126.2 (Ar–CH), 128.2 (Ar–CH),
128.4 (Ar–CH), 128.6 (Ar–CH), 128.8 (Ar–CH), 129.5
(Ar–CH), 130.7 (C, C3N2H3), 133.1 (Ar–CH), 133.9 (Ar–C),
134.3 (Ar–CH), 136.1 (Ar–C), 136.8 (C, C3N2H3), 137.1
(Ar–C), 149.8 (Ar–C), 170.2 (C=O), 196.1 (C=O) ppm; IR
(KBr): ̄ꢀ =3062 (Ar–CH), 2912 (C–H), 1766 (C=O), 1684
(Ar–C=C) cm−1; HRMS (ESI+): m/z calcd for C25H19N3O2
([M+H]+) 394.1556, found 394.1552.
3‑(2‑Oxo‑2‑phenylethyl)‑2‑phenethylisoindolin‑1‑one (4e,
C24H21NO2) Compound 4e was obtained as a yellow solid;
yield 0.13 g (85%); m.p.: 145–146 °C; 1H NMR (400 MHz,
CDCl3): δ=3.09–2.98 (m, 2H, CH2), 3.16 (dd, 1H, J=17.8,
6.9 Hz, CH), 3.29 (dd, 1H, J=17.6, 6.8 Hz, CH), 3.45–3.36
(m, 2H, CH2), 4.14 (dd, 1H, J=17.2, 6.4 Hz, CH), 7.30–7.21
(m, 5H, Ar–H), 7.64–7.40 (m, 5H, Ar–H), 7.93–7.87 (m, 4H,
Ar–H) ppm; 13C NMR (100 MHz, CDCl3): δ=34.5 (CH2),
42.2 (CH2), 42.9 (CH), 55.9 (CH2), 122.7 (Ar–CH), 123.6
(Ar–CH), 126.5 (Ar–CH), 128.2 (Ar–CH), 128.4 (Ar–CH),
128.6 (Ar–CH), 128.8 (Ar–CH), 128.9 (Ar–CH), 131.7 (Ar–
CH), 132.1 (Ar–C), 133.9 (Ar–CH), 136.3 (Ar–C), 138.9
(Ar–C), 145.8 (Ar–C), 168.5 (C=O), 197.3 (C=O) ppm; IR
(KBr): ̄ꢀ =3057 (Ar–CH), 2861 (C–H), 1681 (C=O), 1596
(Ar–C=C) cm−1; HRMS (ESI+): m/z calcd for C24H21NO2
([M+H]+) 356.1651, found 356.1645.
2‑(3‑Methylnaphthalen‑1‑yl)‑3‑(2‑oxo‑2‑phenylethyl)isoin‑
2‑[4‑(4‑Methoxyphenoxy)phenyl]‑3‑(2‑oxo‑2‑phenylethyl)‑
isoindolin‑1‑one (4f, C29H23NO4) Compound 4f was obtained
as a yellow solid; yield 0.12 g (72%); m.p.: 240–241 °C;
1H NMR (400 MHz, CDCl3): δ = 3.42 (dd, 1H, J = 17.9,
7.3 Hz, CH), 3.80 (dd, 1H, J=18.7, 8.9 Hz, CH), 3.85 (s,
3H, OCH3), 6.20 (d, 1H, J = 6.8, 3.1 Hz, CH), 7.06–6.84
(m, 6H, Ar–H), 7.70–7.49 (m, 6H, Ar–H), 7.99–7.93 (m,
4H, Ar–H), 8.24 (d, 1H, J=9.3 Hz, Ar–H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 41.2 (OCH3), 43.7 (CH), 55.7
(CH2), 115.1 (Ar–C), 120.9 (Ar–CH), 121.4 (Ar–C), 122.8
(Ar–CH), 123.9 (Ar–CH), 125.3 (Ar–CH), 125.9 (Ar–CH),
127.7 (Ar–CH), 128.8 (Ar–CH), 128.9 (Ar–CH), 129.5 (Ar–
CH), 132.4 (Ar–C), 133.8 (Ar–CH), 133.9 (Ar–CH), 134.3
(Ar–C), 136.2 (Ar–C), 149.8 (Ar–C), 161.3 (Ar–C), 170.2
(C=O), 196.1 (C=O) ppm; IR (KBr): ̄ꢀ = 3053 (Ar–CH),
2836 (C–H), 1766 (C=O), 1684 (Ar–C=C) cm−1; HRMS
(ESI+): m/z calcd for C29H23NO4 ([M + H]+) 450.1700,
found 450.1698.
dolin‑1‑one (4i, C26H20N2O2) Compound 4i was obtained as
1
a yellow solid; yield 0.1 g (67%); m.p.: 160–162 °C; H
NMR (400 MHz, CDCl3): δ=2.58 (s, 3H, CH3), 3.41 (dd,
1H, J = 15.3, 4.9 Hz, CH), 3.81 (dd, 1H, J= 15.6, 5.8 Hz,
CH), 6.21 (dd, 1H, J=6.6, 3.1 Hz, CH), 7.37 (s, 1H, Ar–H),
7.38 (t, 1H, J = 4.2 Hz, Ar–H), 7.40 (s, 1H, Ar–H), 7.68–
7.46 (m, 8H, Ar–H), 7.99–7.93 (m, 3H, Ar–H), 8.09 (d,
1H, J=8.3 Hz, Ar–H) ppm; 13C NMR (100 MHz, CDCl3):
δ=20.8 (CH3), 29.8 (CH), 43.7 (CH2), 101.7 (Ar–C), 120.6
(Ar–CH), 121.3 (Ar–CH), 122.9 (Ar–C), 123.3 (Ar–CH),
124.8 (Ar–CH), 125.1 (Ar–C), 125.2 (Ar–CH), 125.8 (Ar–
CH), 128.1 (Ar–CH), 128.2 (Ar–CH), 128.9 (Ar–CH), 129.4
(Ar–CH), 129.8 (Ar–CH), 130.1 (Ar–C), 130.6 (Ar–CH),
133.9 (Ar–C), 134.3 (Ar–C), 149.7 (Ar–C), 169.2 (C=O),
196.0 (C=O) ppm; IR (KBr): ̄ꢀ = 3059 (Ar–CH), 2925
(C–H), 1766 (C=O), 1666 (Ar–C=C) cm−1; HRMS (ESI+):
m/z calcd for C26H20N2O2 ([M + H]+) 393.1554, found
393.1560.
3‑(2‑Oxo‑2‑phenylethyl)‑2‑(pyrimidin‑2‑yl)isoindolin‑1‑one
(4 g, C20H15N3O2) Compound 4g was obtained as a pale solid;
yield 0.1 g (65%); m.p.: 190–191 °C; 1H NMR (400 MHz,
CDCl3): δ=3.42 (dd, 1H, J=17.6, 7.4 Hz, CH), 3.81 (dd,
1H, J=17.6, 6.7 Hz, CH), 6.21 (dd, 1H, J=6.8, 2.9 Hz, CH),
7.70–7.49 (m, 9H, Ar–H), 8.00–7.94 (m, 3H, Ar–H) ppm;
13C NMR (100 MHz, CDCl3): δ = 43.7 (CH), 55.9 (CH2),
122.8 (Ar–CH), 123.4 (Ar–CH), 125.8 (Ar–C), 125.9 (Ar–
C), 126.3 (Ar–C), 128.2 (Ar–C), 128.8 (Ar–CH), 129.2 (Ar–
CH), 129.5 (Ar–C), 133.9 (Ar–C), 134.3 (Ar–CH), 136.9
(Ar–C), 149.8 (Ar–C), 170.2 (C=O), 196.6 (C=O) ppm; IR
(KBr): ̄ꢀ =3059 (Ar–CH), 2905 (C–H), 1766 (C=O), 1681
(Ar–C=C) cm−1; HRMS (ESI+): m/z calcd for C20H15N3O2
([M+H]+) 330.1252, found 330.1249.
2‑(Benzo[d]thiazol‑2‑yl)‑3‑(2‑oxo‑2‑phenylethyl)isoindo‑
lin‑1‑one (4j, C23H16N2O2S) Compound 4j was obtained as
1
a yellow solid; yield 0.08 g (65%); m.p.: 142–143 °C; H
NMR (400 MHz, CDCl3): δ=3.81 (dd, 1H, J=17.6, 5.7 Hz,
CH), 4.70 (dd, 1H, J = 17.3, 5.9 Hz, CH), 6.22 (dd, 1H,
J=14.4, 4.5 Hz, CH), 7.83–7.31 (m, 8H, Ar–H), 8.05–7.87
(m, 5H, Ar–H) ppm; 13C NMR (100 MHz, CDCl3): δ=29.7
(CH), 43.7 (CH2), 121.3 (Ar–CH), 121.6 (Ar–CH), 122.8
(Ar–CH), 124.2 (Ar–CH), 124.5 (Ar–C), 124.6 (Ar–CH),
125.7 (Ar–CH), 125.9 (Ar–CH), 126.5 (Ar–CH), 128.2 (Ar–
CH), 128.9 (Ar–C), 129.5 (Ar–CH), 130.6 (Ar–C), 131.2
(Ar–C), 133.9 (Ar–C), 136.2 (Ar–C), 149.8 (Ar–C), 168.9
(C=O), 196.1 (C=O) ppm; IR (KBr): ̄ꢀ = 3057 (Ar–CH),
2926 (C–H), 1766 (C=O), 1686 (Ar–C=C) cm−1; HRMS
1 3

A. M. Jassem, A. M. Dhumad
(ESI+): m/z calcd for C23H16N2O2S ([M + H]+) 385.0960,
found 385.0957.
17. Kundu N, Wahab Khan M, Mahanty J (1999) J Chem Res Synop-
ses 460
18. Zhu C, Falck JR (2012) Tetrahedron 68:9192
19. Bisai V, Unhale RA, Suneja A, Dhanasekaran S, Singh VK (2015)
Org Lett 17:2102
Acknowledgements We gratefully thank Leicester University, UK,
for 1H, 13C NMR, FT-IR, HRMS spectra, and HPLC analysis. We are
also grateful to staf (Department of Zoology and Cytology, Cell and
Molecular Biology Lab, Government College University, Pakistan) for
performing the antimicrobial activity. This work was funded by the
authors.
20. Wu X, Wang B, Zhou S, Zhou Y, Liu H (2017) ACS Catal 7:2494
21. Chen T, Cai C (2017) New J Chem 41:2519
22. Jeon SJ, Li H, Walsh PJ (2005) J Am Chem Soc 127:16416
23. Shen S-C, Sun X-W, Lin G-Q (2013) Green Chem 15:896
24. Polshettiwar V, Varma RS (2008) Chem Soc Rev 37:1546
25. Jassem AM, Dhumad AM, Almashal FA, Alshawi JM (2020) Med
Chem Res 29:1067
26. Jida M, Deprez-Poulain R, Malaquin S, Roussel P, Agbossou-
Niedercorn F, Deprez B, Laconde G (2010) Green Chem 12:961
27. Jida M, Malaquin S, Deprez-Poulain R, Laconde G, Deprez B
(2010) Tetrahedron Lett 51:5109
References
1. Palombi L, Di Mola A, Vignes C, Massa A (2014) Mol Divers
18:323
28. Hügel HM (2009) Molecules 14:4936
29. Jiang B, Shi F, Tu S-J (2010) Curr Org Chem 14:357
30. Jassem AM, Al-Ajely HM, Almashal FAK, Chen B (2019) Russ
J Gen Chem 89:2562
2. Sashidhara KV, Singh LR, Palnati GR, Avula SR, Kant R (2016)
Synlett 27:2384
3. Wu X, Wang B, Zhou Y, Liu H (2017) Org Lett 19:1294
4. Dhanasekaran S, Bisai V, Unhale RA, Suneja A, Singh VK (2014)
Org Lett 16:6068
31. Jassem AM, Almashal FAK, Mohammed MQ, Jabir HAS (2020)
SN Appl Sci 2:359
32. Li J, Li YL, Jin N, Ma AL, Huang YN, Deng J (2015) Adv Synth
Catal 357:2474
5. Stuk TL, Assink BK, Bates RC, Erdman DT, Fedij V, Jennings
SM, Lassig JA, Smith RJ, Smith TL (2003) Org Process Res Dev
7:851
33. Kim K, Hong SH (2015) J Org Chem 80:4152
34. Sgouras D, Maragkoudakis P, Petraki K, Martinez-Gonzalez B,
Eriotou E, Michopoulos S, Kalantzopoulos G, Tsakalidou E, Men-
tis Α (2004) Appl Environ Microbiol 70:518
6. Gai X, Grigg R, Khamnaen T, Rajviroongit S, Sridharan V, Zhang
L, Collard S, Keep A (2003) Tetrahedron Lett 44:7441
7. Carlson JN, Haskew R, Wacker J, Maisonneuve IM, Glick SD,
Jerussi TP (2001) Eur J Pharm 415:181
35. Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL
(2012) Nat Chem 4:90
8. Wrobel J, Dietrich A, Woolson SA, Millen J, McCaleb M, Har-
rison MC, Hohman TC, Sredy J, Sullivan D (1992) J Med Chem
35:4613
36. Lagorce D, Bouslama L, Becot J, Miteva MA, Villoutreix BO
(2017) Bioinformatics 33:3658
37. Cheng T, Zhao Y, Li X, Lin F, Xu Y, Zhang X, Li Y, Wang R, Lai
L (2007) J Chem Inform Mod 47:2140
9. Takahashi T, Nagase T, Sasaki T, Nagumo A, Shimamura K, Miy-
amoto Y, Kitazawa H, Kanesaka M, Yoshimoto R, Aragane K
(2009) J Med Chem 52:3142
38. Molodtsov V, Fleming PR, Eyermann CJ, Ferguson AD, Foulk
MA, McKinney DC, Masse CE, Buurman ET, Murakami KS
(2015) J Med Chem 58:3156
10. Dhanasekaran S, Kayet A, Suneja A, Bisai V, Singh VK (2015)
Org Lett 17:2780
39. Kabalka GW, Yang K, Wang Z (2001) Synth Commun 31:511
40. Rao IN, Prabhakaran E, Das SK, Iqbal J (2003) J Org Chem
68:4079
11. Huang X, Xu J (2009) J Org Chem 74:8859
12. Al-Jaroudi Z, Mohapatra PP, Jha A (2016) Tetrahedron Lett
57:772
41. Han FZ, Su BB, Jia LN, Wang PW, Hu XP (2017) Adv Synth
Catal 359:146
13. Medimagh R, Marque S, Prim D, Marrot J, Chatti S (2009) Org
Lett 11:1817
14. Petronzi C, Collarile S, Croce G, Filosa R, De Caprariis P, Peduto
A, Palombi L, Intintoli V, Di Mola A, Massa A (2012) Eur J Org
Chem 2012:5357
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
15. Srivastava A, Mobin SM, Samanta S (2104) Tetrahedron Lett
55:1863
16. Devineau A, Pousse G, Taillier C, Blanchet J, Rouden J, Dalla V
(2010) Adv Synth Catal 352:2881
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