Study on synthesis of some substituted N-propargyl isatins by propargylation reaction of corresponding isatins using potassium carbonate as base under ultrasound- and microwave-assisted conditions

Article abstract of DOI:10.1007/s11696-021-01697-6

Substituted N-propargyl isatins were synthesized by S_N2 reaction of corresponding substituted isatins with propargyl bromide in the presence of anhydrous K₂CO₃ as base. We reported about study on systematically synthesis of these compounds using heating procedures under different reaction conditions, including microwave-assisted heating conditions at power of 100?W (Procedure A), conventional heating conditions in water bath at 50?°C in acetonitrile (Procedure B), and conventional heating conditions in water bath at 50?°C in DMF (procedure C). The best procedure A was deduced based on the investigations on the reaction conditions. Almost all substituted N-propargyl isatins were new, except compounds with R of H, 5-Me, 5-Cl and 5-Br substituents. The structures of the obtained compounds were confirmed by the modern spectroscopic methods.

Full text of DOI:10.1007/s11696-021-01697-6

Chemical Papers
https://doi.org/10.1007/s11696-021-01697-6
ORIGINAL PAPER
Study on synthesis of some substituted N‑propargyl isatins
by propargylation reaction of corresponding isatins using potassium
carbonate as base under ultrasound‑ and microwave‑assisted
conditions
Nguyen Minh Tri1,2 · Nguyen Dinh Thanh2 · Luong Ngoc Ha2 · Dang Thi Tuyet Anh3 · Vu Ngoc Toan1 ·
Nguyen Thi Kim Giang4
Received: 26 February 2021 / Accepted: 10 May 2021
© Institute of Chemistry, Slovak Academy of Sciences 2021
Abstract
Substituted N-propargyl isatins were synthesized by SN2 reaction of corresponding substituted isatins with propargyl bromide
in the presence of anhydrous K2CO3 as base. We reported about study on systematically synthesis of these compounds using
heating procedures under diferent reaction conditions, including microwave-assisted heating conditions at power of 100 W
(Procedure A), conventional heating conditions in water bath at 50 °C in acetonitrile (Procedure B), and conventional heat-
ing conditions in water bath at 50 °C in DMF (procedure C). The best procedure A was deduced based on the investigations
on the reaction conditions. Almost all substituted N-propargyl isatins were new, except compounds with R of H, 5-Me, 5-Cl
and 5-Br substituents. The structures of the obtained compounds were confrmed by the modern spectroscopic methods.
Keywords 1-Alkyne · Isatins · Propargyl bromide · N-propargylation · Microwave-assisted · Ultrasound-assisted
Introduction
thiosemicarbazones (Muğlu et al. 2019), and hybrid com-
pounds containing simultaneous isatin ring and other het-
erocycles have diverse biological activity (Abdel-Aziz et al.
2017; Al-Wabli et al. 2017; Varun et al. 2019), including
antiviral, antibacterial, anticancer, anticonvulsant and anti-
depressant activity (Gabr et al. 2017; Guo 2019; Pakravan
et al. 2013). Isatin and its derivatives had specifc reactivity
towards electrophiles (Silva et al. 2001; Varun and Kakkar
2019), including alkyl halides (N-alkylation), formaldehyde
and amines (Mannich reaction), halogens (halogenation on
the aromatic nucleus), acyl chlorides or anhydrides (N-acyla-
tion), sulfonyl chlorides (N-sulfonylation).
Isatin (1H-indole-2,3-dione) was frst isolated by Erdmann
and Laurent in 1840 from the oxidation of indigo-colored
chemicals by nitric acid and chromic acid (Silva et al.
2001). Recently, the chemistry of isatin is still of inter-
est to scientists (Singh and Desta 2012) because deriva-
tives of isatin, such as hydrazones (Rabia et al. 2013) and
* Nguyen Dinh Thanh
nguyendinhthanh@hus.edu.vn
1
Department of Toxicological Chemistry and Radiation,
Among the reactions of isatin to diferent agents, the sub-
stitution reactions of hydrogen atom of N–H link on position
N-1 by diferent alkylation agents were particularly impor-
tant (Silva et al. 2001; Varun et al. 2019). Alkylation reac-
tion had been widely used in the synthesis of compounds
with interesting biological activity such as antibacterial,
anticancer, acetylcholinesterase inhibitor, treatment of cer-
tain types of diseases (Guo 2019; Nisha et al. 2014a; Pakra-
van et al. 2013; Varun et al. 2019). The alkylation reaction
was used in order to functionalize isatin and its derivatives.
The alkylation of N-unsubstituted isatins was carried out
Institute for Advanced Technology (Academy of Military
Science and Technology, Vietnam), 17 Hoang Sam, Cau
Giay, Ha Noi, Vietnam
2
Faculty of Chemistry, VNU University of Science (Vietnam
Nation University, Hanoi), 19 Le Thanh Tong, Hoan Kiem,
Hanoi, Vietnam
3
Institute of Chemistry, Vietnam Academy of Science
and Technology, 18 Hoang Quoc Viet, Cau Giay, Ha Noi,
Vietnam
4
Institute of Science and Technology, Ministry of Public
Security of Vietnam, 47 Pham Van Dong, Cau Giay, Ha Noi,
Vietnam
Vol.:(0123456789)
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Chemical Papers
by reaction to alkyl halide in the presence of bases (such as
sodium or calcium hydrides, potassium or cesium carbon-
ates) (Shmidt et al. 2008). Zhungietu et al. used K2CO3 in
DMF for N-alkylation of isatins with alkyl bromides and
iodides and acyl chlorides at room temperature and with
alkyl chlorides at elevated temperatures (70–80 °C) without
ring opening (Radul et al. 1983). Clay et al. utilized KF/alu-
mina for N-alkylation of isatins in acetonitrile (ACN) under
microwave-irradiation at 180 °C (with yields of 91––97%)
or thermally at refux (with yields of 58–88%) (Clay et al.
2012).
et al. 2007b). Alternatively, Azizian et al. reported the use
of microwave irradiation to expedite this process by using
K2CO3/DMF (with yields of 76–94%) or NaOEt/EtOH (with
yields of 24––81%) in a domestic microwave oven (Azizian
et al. 2003). Perillo et al. examined the alkylation of sub-
stituted isatins in the presence of some common inorganic
and organic bases in a range of solvents and found the opti-
mal conditions to consist of K2CO3 or Cs2CO3 and DMF or
N-methyl-2-pyrrolidinone (NMP) (Shmidt et al. 2008). Lind-
sley et al. prepared a variety of substituted N-benzyl isatins
with yields of 20–95% employing K2CO3/KI in acetonitrile
under microwave conditions (160 °C, 10 min) (Bridges et al.
2009), and Go et al. reported an analogous process in DMF
at 150 °C for 5–15 min under microwave irradiation with
product’s yields of 53–96% (Wee et al. 2009).
A variety of methods have been developed for the
N-alkylation of isatins to the target products with high
yields. From literatures, there were two procedures in order
to do this, either the direct Sandmeyer’s synthesis of N-alkyl
isatins from N-alkyl anilines or the N-alkylation of isatins.
The direct synthetic methods involved tedious multistep pro-
cesses which usually give N-alkyl isatins in low to moderate
overall yields. This method must use N-substituted formani-
lides, oxalyl chloride, Hünig’s base to yield N-alkyl isatins
through the oxidation by bromine (Baiocchi et al. 1993;
Meth-Cohn and Goon 1996). The Stolle procedure was con-
sidered the best alternative to Sandmeyer method for the
synthesis of both substituted and unsubstituted isatins (Stollé
1922). Primary or secondary arylamines were condensed
with oxalyl chloride to form a chlorooxalylanilide inter-
mediate which can then cyclize in the presence of a Lewis
acid (such as aluminum trichloride, titanium tetrachloride,
boron trifuoride). More recent approaches to the synthe-
sis of N-substituted isatins involved the direct oxidation of
commercially available, substituted indoles or oxindoles
with diferent oxidizing agents such as iodin and tert-butyl
hydroperoxide in DMSO as solvent (to give isatin N-methyl
and N-benzyl isatins) (Zi et al. 2014), 2-iodoxybenzoic acid-
SO3K in DMSO-water at 60 °C (to give isatin N-methyl
and N-benzyl isatins) (Bredenkamp et al. 2015), oxygen and
tert-butyl nitrite in THF (to give isatin, N-methyl, N-phe-
nyl, N-benzyl, and N-Boc isatins) (Ying et al. 2018). But
these methods could not use for synthesis of isatins with
N-propargyl group because 1-alkyne could be changed under
these reaction conditions. By using this method, the direct
N-alkylation method was performed easily and gave high
yields of N-alkyl isatins (Azizian et al. 2003; Shmidt et al.
2008; Thanh et al. 2016).
Among N-alkyl isatins, N-propargyl isatins played an
important role in the conversion of isatin rings into hybrid
compounds, isatin/1,2,3-triazole hybrid compounds (Jin
et al. 2017; Shaikh et al. 2017; Singh et al. 2017, 2012).
These hybrid compounds were focused in study in recent
years, on the one side due to their ease of synthesis, on the
other, the connection of two heterocycles together over the
bridge linker may bring new remarkable biological activi-
ties or strengthens the inherent activity of each heterocycles
(Jin et al. 2017; Shaikh et al. 2017; Singh et al. 2017, 2012).
Isatin derivatives having azido group or 1-alkyne compo-
nents (N-propargylated isatins) were one of two reagents
necessary for click chemistry (Gupta et al. 2018; MacDon-
ald et al. 2012; Nisha et al. 2014a; Wang et al. 2020). The
synthesis of N-functionalized isatins with propargyl group
made these derivatives to become the 1-alkyne component
in click chemistry. Additionally, N-propargylated isatins
were studied on synthesis and biological evaluations due to
their interesting biological activity, such as activity against
Trichomonas vaginalis (Nisha et al. 2014b), Tritrichomonas
foetus (Nisha et al. 2014a), Staphylococcus aureus, Escheri-
chia coli and Candida albicans (Praveen et al. 2011).
Some authors have reported that substituted N-prop-
argylated isatins could be synthesized by using sodium
hydride (as base) in anhydrous DMF at room temperature;
this procedure was used for N-propargylation of unsubsti-
tuted isatin. Shingate et al. obtained this product with yield
of 85% by using NaH in DMF at room temperature for 2 h
(Shaikh et al. 2017). Kumar et al. reported the synthesis of
some substituted N-propargyl isatins, such as unsubstituted,
Me, Br, Cl, F, NO2 at position 5, with good yields by using
NaH in DMF at room temperature to 60 °C for 2–6 h (Singh
et al. 2012). Unfortunately, there were no data on melting
points and spectra for these compounds. Garden et al. used
calcium hydride as base for N-propargylation of substi-
tuted isatins in DMF at 40 °C for 2–4 h with 92–95% yields
for unsubstituted and 5-nitro isatins (Garden et al. 1998).
Patapoutian et al. used NaH in reaction of unsubstituted
Some of the more general methods include the use of
sodium hydride for substrate activation in nucleophilic
substitution reactions in DMF at 25–80 °C (Tacconi et al.
1973) as well as of calcium hydride in DMF at 40–60 °C for
2–4 h with yields of 21–96% (Garden et al. 1998; Vadivel
et al. 2019) or at 100 °C for 4 h with yield of 89% (Lötter
et al. 2007). Vine et al. used the protocol involving the use
of anhydrous K2CO3 or Cs2CO3 in DMF (r.t. to 80 °C for
5–24 h in the presence of KI with yields of 25–93% (Vine
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Chemical Papers
isatin with propargyl bromide in DMF at 0 °C for 10 h and
obtained a product with yield of 67% (Macpherson et al.
2007). Esteves et al. used sodium hydride in anhydrous
DMF at lower temperature (0–5 °C) for N-propargylation
of unsubstituted isatin with yield of 72% (Silva et al. 2013).
Joubert et al. synthesized unsubstituted N-propargyl isatins
using NaH in DMF under microwave conditions (at 95 °C,
150 W) for 40 min (Tavari et al. 2016). But it’s known that
sodium hydride had dual roles when dimethylformamide or
acetonitrile is used as solvents for these reactions (Hesek
et al. 2009). This agent could behave both as a base and as
a source of hydride (as a reducing agent). In the presence
of an electrophile, such as benzyl bromide, the formation of
by-products could take place. Therefore, Pal et al. performed
the propargylation of unsubstituted isatin by reaction with
propargyl bromide in the presence of anhydrous K2CO3 in
DMF at room temperature for 2 h to give the target prod-
uct with yield of 85% (Rambabu et al. 2013). By using this
procedure with stirring for 4 h, Dawande et al. synthesized
a series of substituted N-propargyl isatins with R=H, 5-Me,
5-Br, 5-Cl, 5-F, but there were not any physical and spectral
data reported (Kahar et al. 2020).
systematically synthesis of substituted N-propargyl isatins
by using K2CO3 as cheaper base (than sodium hydride) in
several solvents (such as DMF, acetone, and acetonitrile)
under diferent reaction conditions, such as microwave-
assisted and/or conventional heating methods, and ultrasonic
irradiation at room temperature (Scheme 1).
Experimental
Melting points were determined in an open capillary tube on
STUART SMP3 (BIBBY STERILIN, UK). The IR spectra were
recorded on FT-IR Afnity-1S Spectrometer (Shimadzu, Japan)
in KBr pellet. The 1H NMR spectra were recorded at 500 MHz
(on Avance AV500 Spectrometer, Bruker, Germany) and at
600 MHz (on AvanceNEO Spectrometer, Bruker, Germany),
and 13C NMR spectra at 125 and 160 MHz, respectively, using
DMSO-d6 as solvent and TMS as an internal standard. ESI mass
spectra were recorded on LC–MS LTQ Orbitrap XL (Thermo
Fisher Scientifc Inc., USA) in methanol/dichloromethane or
methanol using ESI method. The analytical thin-layer chroma-
tography (TLC) was performed on silica gel 60WF254 No. 5715
aluminum sheets (Merck, Germany) with toluene/ethyl acetate
(1:1 by volume) as solvent system, and spots were visualized
directly due to own color of corresponding isatins. All chemi-
cal reagents in high purity (reagent grade for organic synthesis)
As part of our ongoing investigations, we needed a series
of isatin derivatives having N-propargyl group. This fact led
us to explore synthetic methods to obtain (un)substituted
N-propargyl isatins. Thus, in this article, we reported the
Scheme 1. Synthetic path of substituted N-propargyl isatins
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Chemical Papers
were purchased from the Merck Chemical Company. The micro-
wave-assisted reactions were performed in Microwave (MW)
Synthesis Reactor Discover 2.0 (CEM Corporation, USA).
acetate, the extract was dried with anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The
product was recrystallized from 96% ethanol to N-propargyl
isatins 4a.
General procedure for synthesis of substituted
N‑propargyl isatins 4a‑m
Procedure A: MW‑assisted heating conditions at power
of 100 W in anhydrous DMF
Procedure for the optimization of the reaction conditions
To a solution of appropriate substituted isatins 3a–m (1 mmol)
was added anhydrous K2CO3 (1.5 mmol, 207 mg) in anhy-
drous DMF (2 mL) in microwave vessel. Propargyl bromide
(1.5 mmol, 0.167 mL of solution 80 wt% in toluene) was then
added into this suspension mixture. The reactants were mixed
well, and the mixture was irradiated in microwave oven at power
of 100 W for appropriate time at 50 °C (see Table 2). The reac-
tion process was monitored by TLC. After the reaction was com-
pleted, the mixture was cooled to room temperature, and water
was added to the mixture to dissolve inorganic salts (K2CO3 and
KBr). The product was extracted with ethyl acetate, the extract
was dried with anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. The residue was crystallized
from 96% ethanol to aford the title substituted N-propargyl isat-
ins 4a–m.
A solution of unsubstituted isatins 3a (1 mmol, 147 mg) and
propargyl bromide (1.5 mmol, 0.167 mL of solution 80 wt%
in toluene) was dissolved in appropriate solvent in micro-
wave vessel (see Table 1). Anhydrous K2CO3 (1.5 mmol,
207 mg) was added. The investigations of reaction condi-
tions in order to fnd the optimal reaction conditions were
carried out according to the data on reaction conditions (sol-
vent volume, microwave or ultrasound irradiation time, or
refux heating time) that were represented in Table 1. The
reaction process was monitored by thin-layer chromatogra-
phy (TLC, solvent system of toluene/ethyl acetate, 1:1 by
volume). After reaction completion, the solvent or removed
under reduced pressure (for acetone and acetonitrile) or
water in the same volume was added to dissolve inorganic
salts (K2CO3 and KBr). The product was extracted with ethyl
Table 1 Optimization of reaction conditions for the synthesis of N-propargyl isatin (4a)
Entry
Reaction conditions
Solventa
Volume of solvent
(mL)
Reaction time
Yield of 4a (%)b
1
2
3
4
5
6
7
8
MW-assisted (at 100 W)
Acetone
Acetonitrile
DMF
4
4
2
N.A.c
16 min
5 min
18 min
2.5 h
2 h
2 h
2.5 h
1 h
N.A
10.8
97.2
21.6
DMSO
2
d
Water bath at 50 °C
Acetone
Acetonitrile
DMF
10
10
10
10
5
5
5
–
91.9
92.9
86.5
DMSO
d
9
Ultrasound-assisted at 50 °C
Acetone
Acetonitrile
DMF
–
10
11
12
3 h
11 h
11 h
75.7
71.4
52.4
DMSO
5
aAll solvents were dried before used
bIsolated yield
cN.A.: not application
dBy-products were obtained
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Chemical Papers
Table 2 Synthesis of substituted
N-propargyl isatins (4a–m)
Compd
Procedure Aa
Procedure Ba
Procedure Ca
M.p. (°C)
Reaction
Yield (%)b
Reaction
time (h)
Yield (%)b
Reaction
time (h)
Yield (%)b
time (min)
4a
4b
4c
4d
4e
4f
5
5
5
7
5
5
5
5
7
5
5
5
5
97.2
79.4
85.2
90.6
93.0
95.7
93.5
98.7
91.1
97.0
91.0
97.0
99.5
2
6
3
3
7
3
3
3
2
2
3
2
2
91.9
99.5
94.9
84.5
98.0
84.5
87.3
98.5
72.7
99.3
90.9
76.2
99.1
2
6
6
8
6
6
6
6
12
6
92.9
54.2
74.1
72.7
76.4
99.0
99.0
98.0
43.3
90.2
75.7
83.6
73.8
156–158c
155–157
170–172
168–170
170–172
97–98
144–146
153–154
124–125
160–162
128–130
110–112
154–155
4g
4h
4i
4j
4k
4l
29
24
12
4m
aProcedure A: MW-assisted heating conditions at power of 100 W, solvent: anhydrous DMF (2 mL); Pro-
cedure B: Under conventional heating conditions in water bath at 50 °C, solvent: anhydrous acetonitrile
(5 mL); Procedure C: Under conventional heating conditions in water bath at 50 °C, solvent: anhydrous
DMF (10 mL)
bIsolated yield
c157–158 °C (Garden et al. 1998), 156–158 °C (Shaikh et al. 2017), 152–155 °C (Silva et al. 2013), 156–
157 °C (Rambabu et al. 2013)
Procedure B: Under conventional heating conditions
in water bath at 50 °C in anhydrous acetonitrile
process was monitored by TLC. The solvent was then evapo-
rated completely in vacuum at 50°. After the reaction was
completed, the reaction mixture was treated with the same
methods that used in Procedure A. The separated solid prod-
uct was fltered, washed by water and recrystallized from
mixture of 96% ethanol to aford the title N-propargyl isatins
4a–m.
To a solution of appropriate substituted isatins 3a–m
(1 mmol) was added anhydrous K2CO3 (1.5 mmol, 207 mg)
in anhydrous acetonitrile (10 mL) in microwave vessel. Pro-
pargyl bromide (1.5 mmol, 0.167 mL of solution 80 wt%
in toluene) was then added dropwise into the suspension
mixture. The reaction mixture was heated under refux while
stirring at 50 °C in water bath for 2–7 h (see Table 2). When
the reaction was accomplished (monitored by TLC.), the
solvent was evaporated completely under reduced pressure
at 50 °C. After the reaction was completed, the reaction mix-
ture was treated with the same method that used in Proce-
dure A. The residue was crystallized from 96% ethanol to
aford the title substituted N-propargyl isatins 4a–m.
The characterizations of some representative N-propargyl
isatins were as follows.
N‑Propargylisatin (4a)
From 3a (1 mmol, 147 mg). Orange solids.
Yield 97.2% (Procedure A), 91.9% (Procedure B), 91.9%
(Procedure C). IR (KBr), ν (cm–1): 3259, 3088, 3064, 2962,
1735, 1612, 1463, 1340, 1089, 1035, 929, 759; 1H NMR (δ,
ppm): 7.72 (t, J=7.5 Hz, 1H, H-6), 7.59 (d, J=7.5 Hz, 1H,
H-4), 7.23 (d, J=7.5 Hz, 1H, H-7), 7.18 (t, J=7.5 Hz, 1H,
H-5), 4.55 (d, J = 2.0 Hz, 2H, N-CH2C≡CH), 3.33 (t,
J=2.5 Hz, 1H, N-CH2C≡CH); 13C NMR (δ, ppm): 182.5
(C-3), 157.3 (C-2), 149.4 (C-7a), 138.1 (C-6), 124.5 (C-5),
123.6 (C-4), 117.6 (C-3a), 111.1 (C-7), 77.3 (N-CH2C≡CH),
74.9 (N-CH2C≡CH), 29.0 (N-CH2C≡CH); ESI-HRMS(+):
Procedure C: Under conventional heating conditions
in water bath at 50 °C in anhydrous DMF
To a suspension of appropriate substituted isatins 3a–m
(1 mmol) was added anhydrous K2CO3 (1.5 mmol, 207 mg)
in anhydrous DMF (10 mL) in microwave vessel. Propargyl
bromide (1.5 mmol, 0.167 mL of solution 80 wt% in toluene)
was then added dropwise into the suspension mixture. The
reaction mixture was heated under refux while stirring at
50 °C in water bath for 2–29 h (see Table 2). The reaction
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Chemical Papers
C11H7NO2, calcd. for. M + H = 186.0549 Da,
M + Na = 208.0369 Da, found: m/z 186.0554 [M + H]+,
208.0377 [M+Na]+.
(25 °C, 50 °C, and 70 °C) in anhydrous DMF, we found
that the most appropriate procedure for preparation of these
compounds was about 50 °C when anhydrous K2CO3 was
used as base. The lower reaction temperatures needed the
extended reaction time. The reaction time required about
30 h if the reaction was carried out at room temperature.
The higher reaction temperatures led to the decomposition
of products formed, and caused some problems for isolat-
ing and purifying the reaction products. These increasing
of reaction temperature led to formation of undefned by-
products or oily/tar substances having indefnite structures.
Other different solvents, such as DMSO, acetone, and
acetonitrile, were excellent solvents used for SN2 reaction
(Hamlin et al. 2018). Therefore, we had performed the opti-
mization of reaction conditions for the conversion of isatins
into the corresponding N-propargyl isatin compounds. The
reaction of unsubstituted isatin 3a with propargyl bromide
was used as a model reaction for this purpose. Anhydrous
K2CO3 was used as a base. Applied heating conditions were
microwave (MW)-assisted heating conditions at power of
100 W, ultrasound-assisted heating conditions in water bath
at 50 °C, and conventional heating conditions in water bath
at 50 °C. (Table 1).
5‑Chloro‑N‑propargylisatin (4f)
From 3f (1 mmol, 182 mg). Yellow solids. Yield 97.0%
(Procedure A), 99.3% (Procedure B), 90.2% (Procedure C).
IR (KBr), ν (cm–1): 3224, 3105, 3068, 2964, 1726, 1606,
1473, 1442, 1327, 1263, 1176, 1122, 1033, 825; 1H NMR
(δ, ppm): 7.76 (dd, J=2.0, 8.5 Hz, 1H, H-6), 7.63 (d, 1H,
J=2.0 Hz, H-4), 7.26 (d, J=8.0 Hz, 1H, H-7), 4.56 (d, 1H,
J = 2.5 Hz, N-CH2C≡CH), 3.34 (dd, J = 2.5, 5.0 Hz, 1H,
N-CH2C≡CH); 13C NMR (δ, ppm): 181.9 (C-3), 157.6
(C-2), 148.4 (C-7a), 137.5 (C-5), 128.4 (C-6), 124.5 (C-4),
119.5 (C-7), 113.3 (C-4a), 77.5 (N-CH2C≡CH), 75.6
(N-CH2C≡CH), 29.6 (N-CH2C≡CH); ESI-HRMS( +):
C11H635ClNO2/C11H637ClNO2, calcd. for. (M+H)/(M+2+
H)=220.0160/222.0130 Da, found: m/z 220.0182/222.0157
[M+H]+/[M+2+H]+.
Results and discussion
From Table 1, it’s showed that acetone (Entries 1, 5, and
9) was not appropriate as a solvent for propargylation of
isatins under applied reaction conditions as shown. Under
MW-assisted conditions, solvents such as acetonitrile (Entry
2) and DMSO (Entry 4) gave low yields (10.8% and 21.6%,
respectively), although the MW irradiation at power of
100 W at 50 °C was performed until 16 min and 18 min,
respectively. The highest yield was achieved (92.9%) when
DMF was used as a solvent with time only 5 min (Entry 3).
We found that the raising the power of microwave irradiation
(from 100 W up to 180 W) and the lengthening irradiation
time made the reaction mixture become the tar form com-
pletely (maybe, including reactants, product, and by-prod-
ucts). However, the levels of decomposition of the products
were diferent, as compounds 4a, 4b, 4e were decomposed
completely, while compound 4j, 4k was decomposed only a
part, and compounds 4c, 4d still obtained the product with
the moderate yields, however, they are black possibly due
to some tar.
The synthesis of N-propargyl isatins was performed
according to Scheme 1. Substituted isatins 3b–m were
synthesized from substituted anilines 1b–l by using the
Sandmeyer’s methodology through substituted α‐isoni-
trosoacetanilides 2b–l (except unsubstituted isatin 3a is
commercially available) (Pirrung et al. 2005; Sandmeyer
1919; Vine et al. 2007a). 5,7-Dibromoisatin (3 m) was syn-
thesized by bromination of unsubstituted isatin 3a using
bromine in glacial acetic acid according to literature pro-
cedure (Vine et al. 2007a). Propargyl derivatives of isatins
4a–m were obtained by alkylation of substituted isatins
3a–m using propargyl bromide and anhydrous K2CO3 as a
base in appropriate solvents for SN2 reaction, such as DMF,
DMSO, acetonitrile, or acetone, under diferent rection
conditions (Scheme 1, Table 1). We applied our previous
procedure in synthesis of N-alkyl isatins for this purpose
(Thanh et al. 2016). The procedure for synthesis of N-pro-
pargyl isatin derivatives 4a–m was based on combination
and improvement of the literature procedures (Garden et al.
1998; Shmidt et al. 2008; Thanh et al. 2016), involving an
initial base-assisted N-alkylation of substituted isatins with
propargyl bromide to yield the corresponding N-propar-
gyl isatins. However, the presence of terminal triple bond
caused these reaction conditions to be applied with a few
improvements.
Under conventional heating conditions at 50 °C in water
bath, both solvents, acetone (Entry 6) and DMF (Entry 7),
gave the high yields (91.9% for acetone v.s. 92.9% for DMF)
with same reaction times (for 2 h). Solvent DMSO (Entry 8)
gave lower yield (86.5%) with longer reaction time (2.5 h).
Ultrasonic methods proved to be unsuitable for this reac-
tion, in addition to acetone (to give unwanted byproduct),
both solvents, acetonitrile (Entry 10) and DMF (Entry 11),
gave the same yields (75.7% vs 71.4%, respectively), but
acetonitrile was the better option, since the higher yield
was achieved for shorter reaction time (3 h vs 11 h for each
By initially investigating the reaction of unsubstituted
isatin 3a with propargyl bromide was used as a model reac-
tion with propargyl bromide in the presence of two bases
(NaH and anhydrous K2CO3) and at diferent temperatures
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Chemical Papers
corresponding solvent), on the other hand, acetonitrile, with
a lower boiling point, was easier to treat the reaction than
DMF (easily removed from the reaction mixture by reduced
distillation). When DMSO (Entry 12) was used as reaction
solvent, the lower yield (52.4%) was attained after ultra-
sound irradiation for 11 h.
two protons of methylene group (with coupling constants
J=2.0–2.5 Hz in cases of doublet, triplet or doublet of dou-
blets patterns). The triple carbon–carbon bond was located
in regions at δ=79.3–77.0 ppm and δ=75.6–74.8 ppm, and
belonged to the terminal and internal carbon atoms in triple
carbon–carbon bond, respectively. Methylene-propargylic
group had signals at δ=31.9–29.0 ppm.
Because the ultrasonic procedure at 50 °C gave much
lower yields than the MW and conventional heating in DMF
and acetonitrile at 50 °C procedures (75.7 and 71.4% vs
97.2, 91.9 and 92.9%), we only use these three procedures
to synthesize the remaining compounds without using the
ultrasonic procedure. Therefore, the optimal reaction condi-
tions were anhydrous DMF as solvent under MW-assisted
conditions at power of 100 W for 5 min irradiation. Other
suitable reaction conditions that could be applied were anhy-
drous acetonitrile or anhydrous DMF under conventional
heating in water bath at 50 °C for 2 h. Anhydrous potas-
sium was used as a base. These conditions were used for
the synthesis of other substituted N-propargyl isatins 4b–m
(Table 2). In the procedure A, MW-assisted heating condi-
tions at power of 100 W in anhydrous DMF, the reaction
yields were achieved from 79.4% up to 97.2% for 5–7 min.
In the procedure B, under heating conditions in water bath
at 50 °C, in anhydrous acetonitrile, the reaction yields were
72.7–99.5%, but the reaction time lengthened until 2–7 h.
Procedure C, under heating conditions in water bath at 50 °C
in anhydrous DMF, gave the similar yields (72.7–99.0%),
except the cases of compounds 4b and 4i (with yields of
54.2% and 43.3%, respectively), but the reaction time length-
ened more, until 6–29 h, except the case of compound 4a
(for 2 h). Thus, procedure A was more favorable than pro-
cedures B and C because the reaction process in A required
shorter time intervals yet gave similar yields as B and C.
These obtained propargyl derivatives of isatins were
in yellow or orange solid forms, soluble easily in com-
ment organic solvents (ethanol, methanol, DMF, DMSO,
acetone, toluene…), insoluble in water, having high melt-
ing points. The purifcation of the reaction mixture, after
usual work up, by recrystallization or column chromatog-
raphy resulted in the isolation of desired scafolds, and the
structures were assigned based on spectral data (see Sec-
tion 1 in “Supplementary Data” in online version of this
article). The presence of propargylic group was confrmed
by the strong band at ῡ = 3286–3224 cm−1 belonged to
stretching vibration of terminal alkyne C–H bond; other
weak band in region at ῡ = 2121–2117 cm−1 belonged to
carbon–carbon triple bond of propargylic-tethered group of
isatin ring. In 1H NMR of these isatins, protons in methylene
group of N-propargyl substituent had resonance signals at
δ=4.68–4.52 ppm, usually in doublet coupling pattern due
to the coupling interaction with propargylic proton (with
coupling constants of J = 2.0–2.5 Hz). The 1-alkyne pro-
ton at δ = 3.41–3.33 ppm had coupling interactions with
All above discursions on spectroscopic characteristics
asserted the structure of obtained N-propargyl isatin 4a–m.
These spectroscopic data are consistent with the values of
published similar compounds (Garden et al. 1998; Kahar
et al. 2020; Macpherson et al. 2007; Rambabu et al. 2013;
Shaikh et al. 2017; Singh et al. 2012; Tavari et al. 2016).
Conclusions
Substituted N-propargyl isatins were readily prepared by
propargylation reaction of corresponding substituted isat-
ins using anhydrous K2CO3 as base in anhydrous DMF or
acetonitrile. Three heating methods were applied, and all
gave the similar yields of compounds 4a–m, but procedure
A was favored because the reaction times in this procedure
were shorter than in procedures B and C. We hoped that
these synthesized substituted N-propargyl isatins will be
important initial materials for further studies in the synthe-
sis of compounds with isatin ring, including the synthesis
of 1,2,3-triazole-isatin hybrid compounds by using click
chemistry.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11696-021-01697-6.
Acknowledgements This research is funded by Vietnam National
Foundation for Science and Technology Development (NAFOSTED)
under Grant Number 104.01-2020.01.
Declarations
Conflict of interest The authors declare no confict of interest.
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