Trifluoroethanol and liquid-assisted grinding method: a green catalytic access for multicomponent synthesis

Article abstract of DOI:10.1007/s11164-017-3206-y

An efficient and versatile mechanochemical route for the synthesis of chromene and isoindolo[2,1-a]quinazoline scaffolds has been developed via a simple mortar and pestle liquid-assisted grinding method using 2,2,2-trifluoroethanol (TFE) as an efficient catalyst. The present protocol is very efficient as it offers reaction in mild reaction condition, cleaner reaction profiles, effortless work-up step with excellent purity, and high yield of the desired products with short reaction time.

Full text of DOI:10.1007/s11164-017-3206-y

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3206-y
Trifluoroethanol and liquid-assisted grinding method:
a green catalytic access for multicomponent synthesis
Trushant Lohar1 Ananda Mane1 Siddharth Kamat1
•
•
•
Arjun Kumbhar1 Rajashri Salunkhe1
•
Received: 9 August 2017 / Accepted: 17 November 2017
Ó Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract An efficient and versatile mechanochemical route for the synthesis of
chromene and isoindolo[2,1-a]quinazoline scaffolds has been developed via a
simple mortar and pestle liquid-assisted grinding method using 2,2,2-trifluo-
roethanol (TFE) as an efficient catalyst. The present protocol is very efficient as it
offers reaction in mild reaction condition, cleaner reaction profiles, effortless work-
up step with excellent purity, and high yield of the desired products with short
reaction time.
Keywords Liquid assisted grinding Á Trifluoroethanol Á Chromenes Á Isoindolo[2,1-
a]quinazolines
Introduction
Over the last few years, fluorinated compounds have attracted great interest in
organic synthesis due to their favorable properties like low boiling points and high
melting points compared with their non-fluorinated counterparts. In addition, they
have high polarity and strong hydrogen bond donation which increase their ability to
solvate water molecules [1]. Special attention has been paid to 2,2,2-trifluoroethanol
(TFE) as its strong electron-withdrawing CF3 group affects the course of reactions
when it is used as a solvent. As TFE is acting as a Brønsted acid, the organic
reactions in TFE are generally selective and carried out without using any catalysts.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
017-3206-y) contains supplementary material, which is available to authorized users.
&
Rajashri Salunkhe
rsschem1@gmail.com
1
Department of Chemistry, Shivaji University, Kolhapur, M.S. 416004, India
123

T. Lohar et al.
In addition, it works under mild conditions, allowing a facile isolation of the final
product simply by distillation of TFE [2]. Nowadays, TFE has been used in various
organic transformations as a catalytic platform for the synthesis of heterocyclic
scaffolds [3, 4]. In addition, it has also been used in various catalytic processes such
as oxidation [5], protection and deprotection of amine groups [6], cyclopropanation
of alkenes, and oxirane ring-opening reactions [7, 8].
Green chemistry focuses on research that attempts to develop safe and
environmentally friendly chemical operations for the design of biologically active
and industrially important molecules in synthetic organic chemistry [9–12]. The
green chemistry concept offers many alternative approaches to carry out organic
transformations under environmental benign conditions including use of less
solvents, high atom economy, and selectivity, elimination of toxic waste, use of
ambient, more facile ways of product separation and purification and use of
alternative energy sources [13–20]. One of the protocols belonging to this
sustainable and ‘‘greener’’ concept is ‘mechanosynthesis’ by using ‘‘ball milling’’
or simple grinding methods [21, 22]. Manual grinding using a mortar and pestle is a
very useful method at the laboratory scale, due to its simple experimental setup.
This technique does not require external heating, hence is an energy efficient and
more economical and ecologically favorable procedure in organic synthesis [23].
The work carried out by Toda and co-workers showed that many of the exothermic
organic reactions can be performed in good yields using grinding by mortar and
pestle [24, 25]. This technique is mostly used for condensation reactions including
Schiff’s base formation and oxime formation [26, 27]. Recently, it has been found to
be equally effective for the construction of heteroaromatic compounds of biological
interest [28–30].
Heterocyclic motiffs like chromenes and isoindolo[2,1-a]quinazolines are rapidly
gaining importance in synthetic and natural product chemistry [31–33]. They have
also been employed as an intermediate for the synthesis of heterocycles [34, 35] and
selective organic oxidants under mild conditions [36]. A detailed literature survey
indicated that the synthesis of chromene cores was reported by the condensation of
salicylaldehyde and 1,3-dicarbonyl compounds using I2 [37], FeCl3Á6H2O [38] and
sulfamic acid [39]. These known methods have their own merits and demerits from
the environmental and economic points of view.
Isoindolo[2,1-a]quinazoline is a prevalent heterocycle formed by the fusion of
indole and quinazoline nuclei. These compounds are most versatile building blocks
for the synthesis of various pharmaceuticals such as Batracylin and natural products
like Tryptanthrin, Luotonin A, and Rutaecarpine [40]. Structurally, these molecules
contain quinazolinone and isoindolone cores which synchronize to have astonishing
biological properties [41, 42]. Isoindolo[2,1-a]quinazoline derivatives are the strong
inhibitors of tumor necrosis factor-alpha which is one of the key cytokine mediators
used as a marker for many inflammatory disorders such as rheumatoid arthritis,
Crohn’s disease and ulcerative colitis [43]. The interesting structural pattern of
isoindolo[2,1-a]quinazolines coupled with its multifaceted pharmacological poten-
tial has motivated chemists to explore this useful scaffold [44–47].
Inspired by the characteristic properties of TFE and in continuation of our efforts
to develop green chemistry methodology [48, 49], we report herein an efficient
123

Trifluoroethanol and liquid-assisted grinding method…
alternative energy input for the multicomponent synthesis of chromenes and
isoindolo[2,1-a]quinazolines under the catalytic umbrella of trifluoroethanol (TFE)
within short reaction times.
Experimental
Solvents and reagents were of AR grade commercially sourced from Sigma Aldrich
and used without further purification. Melting points were determined in an open
capillary and are uncorrected. Infrared spectra were measured on a Perkin Elmer
FT-IR spectrophotometer. The samples were examined as KBr discs * 5% w/w.
1
NMR spectra were recorded on a Bruker AC (300 MHz for H NMR and 75 MHz
for 13C NMR) spectrometer using CDCl3 and DMSO as solvents.
General procedure for the synthesis of chromene scaffolds (3a–3l)
A mixture of CH activated acids such as 1H-indene-1,3(2H)-dione or dimedone or
barbituric acid (2 mmol), salicylaldehydes (1 mmol) and TFE (0.5 mL) was gently
ground in a mortar and pestle. The reaction mixture turns to pasty mass after
5–7 min of grinding. The grinding was continued for the times mentioned in
Table 3 (see ‘‘Results and discussion’’). The progress of the reaction was monitored
by thin layer chromatography (TLC). In some cases, 0.2 mL of TFE was added after
7 min to facilitate complete conversion. After the completion of the reaction, the
reaction mixture was washed with cold water, and then filtered to obtain the pure
products.
General procedure for the synthesis of isoindolo[2,1-a]quinazolines (4a–4l)
A mixture of an equimolar quantities of 2-aminobenzamides (1 mmol), 2-carboxy-
benzaldehyde (1 mmol) and TFE (0.5 mL) was ground together for 9–11 min using
a mortar and pestle at room temperature. The progress of the reaction was monitored
by TLC. After the completion of the reaction, the reaction mixture was washed with
petroleum ether followed by CHCl3, and then filtered to obtain the pure products.
Spectral data of compounds
2-(11-Oxo-10,11-dihydroindeno[1,2-b]chromen-10-yl)-1H-indene-1,3(2H)-dione (3a)
(Table 3, Entry 1) 1H NMR (300 MHz, CDCl3):
d 3.72–3.73 (d, 1H,
J = 2.5 MHz, CH), 4.88–4.89 (d, 1H, J = 2.5 MHz, CH), 6.95–6.99 (m, 1H),
7.11–7.13 (d, 1H, J = 7.5 MHz), 7.21–7.22 (m, 2H), 7.31–7.31 (m, 1H), 7.37–7.44
(m, 3H), 7.74–7.81 (m, 2H), 7.83–7.86 (m, 1H), 7.94–7.96 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 29.3, 57.4, 105.3, 117.1, 117.6, 120.3, 120.6, 122.0, 124.6,
127.8, 127.9, 129.3, 131.3, 134.3, 134.6, 135.8, 141.2, 141.9, 150.1, 169.7, 191.4,
197.0, 198.0.
123

T. Lohar et al.
2-(8-Chloro-11-oxo-10,11-dihydroindeno[1,2-b]chromen-10-yl)-1H-indene-1,
3(2H)-dione (3b) (Table 3, Entry 2) 1H NMR (300 MHz, CDCl3): d 3.68–3.69
(d, 1H, J = 2.5 MHz, CH), 4.82–4.83 (d, 1H, J = 2.5 MHz, CH), 7.14 (s, 1H),
7.16–7.21 (m, 2H), 7.30–7.37 (m, 2H), 7.38–7.44 (m, 2H), 7.78–7.82 (m, 2H),
7.87–7.91 (m, 1H), 7.94–7.97 (m, 1H); 13C NMR (75 MHz, CDCl3): d 29.2, 57.5,
104.8, 117.6, 118.4, 120.8, 122.2, 122.6, 122.9, 123.8, 127.3, 127.8, 127.9, 128.5,
129.5, 129.7, 131.2, 131.4, 133.9, 134.5, 134.8, 135.5, 141.1, 141.8, 148.7, 169.4,
191.0, 196.6, 197.5.
5-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-chromeno[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,
6(1H,3H,5H)-trione (3g):(Table 3, Entry 7) 1H NMR (300 MHz, DMSO-d6): d
3.85–3.86 (d, 1H, J = 2.5 MHz, CH), 4.71–4.72 (d, 1H, J = 2.0 MHz, CH),
7.08–7.10 (d, 1H, J = 8.0 MHz), 7.14–7.15 (d, 1H, J = 7.5 MHz), 7.20–7.23 (m,
1H), 7.32–7.36 (m, 1H), 10.98 (s, 1H, NH), 11.17 (s, 1H, NH), 11.28 (s, 1H, NH),
11.97 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 33.0, 52.7, 84.6, 115.9, 120.3,
125.0, 127.5, 128.6, 148.6, 149.0, 149.9, 154.8, 162.9, 168.3, 169.0.
6-Phenyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (4a) (Table 6, Entry
1) 1H NMR (300 MHz, CDCl3): d 6.13 (s, 1H), 7.28–8.33 (m, 13 H); 13C NMR
(75 MHz CDCl3) d 69.3, 119.2, 120.1, 120.9, 121.8, 125.8, 123.6, 126.7, 128.9,
129.5, 133.4, 134.6, 138.2, 139.8, 163.3, 166.4 ppm.
6-(4-Methyl)-6,6a-dihydro-isoindolo[2,1-a]quinazoline-5,11-dione (4c) (Table 6,
Entry 3) 1H NMR (300 MHz, CDCl3):d 2.40 (s, 3H), 6.17 (d, J = 7.6 Hz, 1H),
6.28 (s, 1H), 7.20–7.28 (m, 4H), 7.40–7.58 (m, 4H), 7.91 (d, J = 7.6 Hz, 1H),
8.07–8.18 (m, 2H) ppm; 13C NMR (75 MHz CDCl3): d 21.0, 71.7, 120.0, 124.1,
124.9, 125.2, 129.1, 129.4, 130.0, 130.1, 131.8, 132.2, 133.4, 133.9, 134.9, 136.7,
138.2, 138.9, 164.0, 164.9 ppm.
Results and discussion
Initially, we performed multicomponent synthesis of chromenes by the reaction of
salicylaldehyde and 1,3 dicarbonyl compounds using TFE via a liquid-assisted
grinding (LAG) method (Scheme 1).
In preliminary optimization experiments, we examined whether grinding under
neat or under LAG condition is more effective by reacting salicylaldehyde (1 mmol)
and 1H-indene-1,3(2H)-dione. Initially, the reactants were placed in an agate mortar
and ground gently with a pestle under neat condition at ambient temperature
(25–28 °C) (Table 1, entry 1). It was observed that the reaction produces a sticky
solid mass after 10 min, which involves intermediate adduct, unreacted starting
materials and a trace amount of the desired product, as observed by TLC. The
reason behind the incomplete reaction was that, as some unreacted starting materials
were trapped inside the solid mass, further reaction became sluggish under neat
condition. Fortunately, an addition of a small amount of TFE into the same reaction
mixture accelerated the rate of formation of the desired product to a great extent. It
was observed that the added TFE could dissolve a major part of the solid
123

Trifluoroethanol and liquid-assisted grinding method…
Scheme 1 Synthesis of chromene scaffolds using TFE under LAG method
intermediates and, thereby, release the trapped starting materials to facilitate their
complete conversion to the desired product.
It is well known that liquid-assisted grinding often brings out better results than
‘‘dry’’ grinding [50]. Therefore, we used various common organic solvents for LAG,
and the percentage of isolated yields of the desired product was analyzed to find out
the solvent of choice (Table 1, entries 2–7). In this regard, 0.5 mL of TFE was
found to be the most suitable in terms of yield and rate of the reaction (Table 1,
entry 8).
In order to further show the efficiency of our protocol, a comparison with
available reported protocols in the literature was carried out (Table 2). The data
showed that the superior efficiency, environment compatibility and practical
applicability of our protocol in comparison to reported procedures.
123

T. Lohar et al.
Table 1 Optimization of reaction conditions
Entry
Solvent
Time (min)
Yielda %
1
2
3
4
5
6
7
8
Neat
10
10
10
10
10
10
10
08
20
20
20
25
30
32
32
88
CH3CN
EtOAc
H2O
Methanol
Ethanol
2-Propanol
TFE
Reaction conditions: salicylaldehyde (1 mmol) and 1H-indene-1,3(2H)-dione, TFE (0.5 mL) at R.T.
(25–28 °C)
aIsolated yields
Table 2 Comparison of the efficiency of TFE/LAG method with reported procedures
Entries
Catalyst
Reaction conditions
Time (min)
Yield (%)
References
1
2
3
I2
Ethanol/reflux
Ethanol/water
Grinding/RT
30
60
08
85
92
88
[37]
Sulfamic acid
TFE
[39]
This work
The plausible mechanism for the formation of chromenes is depicted in
Scheme 2. The mechanism involves two plausible reaction pathways (Route A and
Route B). TFE acts as a Brønsted acid and plays a significant role in increasing the
electrophilic character of the salicylaldehyde. In addition, the polar transition state
of the reaction could be well stabilized by the high ionizing solvent TFE. The first
step involves the formation of a Knoevengel adduct via Knoevengel condensation of
salicylaldehyde and 1H-indene-1,3(2H)-dione. The adduct undergoes cyclization
via dehydration to form intermediate-I, which further undergoes Michael-type
attack by a second molecule of 1H-indene-1,3(2H)-dione followed by auto-
oxidation to furnish the final product.
The proposed mechanism is also supported by 1H NMR analysis of intermediate-
1
I (see ESI, Fig. 1, ). In the H NMR spectrum, a remarkable singlet at d 2.40 ppm
for methine proton confirms the cyclization of the product. Also, an olefinic proton
([ C=CH–Ar) appears at d 9.68 ppm. The eight protons of the aromatic ring
123

Trifluoroethanol and liquid-assisted grinding method…
Scheme 2 Plausible mechanism for the synthesis of chromenes
appears as multiplets between d 7.02 and d 8.10 ppm. From NMR analysis, it is
concluded that synthesis of chromenes follows the Route A type mechanism.
To test the generality of this method, a series of substituted salicylaldehydes were
treated with 1,3-dicarbonyl compounds such as 1H-indene-1,3(2H)-dione, dimedone
and barbituric acid under optimized reaction conditions. It was observed that the
salicylaldehydes containing electron-donating (Table 3, entries 3 and 6) as well as
electron-withdrawing groups (Table 3, Entries 2, 5 and 9) participated in the
reaction uniformly in terms of the product yields. The method was also found to be
123

T. Lohar et al.
Table 3 Synthesis of chromene scaffolds using TFE under LAG method
Sr.
Salicylaldehydes
Product
Time
(min)
Yielda
(%)
M.P.
(oC) [L]b
No.
HO
C
1.
11
88
176-178
[178-180]37
O
O
O
OH
O
3a
l
C
HO
C
2.
12
87
177-178
[176-178]37
O
O
O
OH
Cl
O
3b
e
M O
HO
C
3.
11
87
198-200
[199-201]37
O
O
O
OH
M
e
O
O
3c
HO
C
OH
O
O
4.
5.
12
88
203-205
[205-206]38
OH
O
3d
l
C
HO
C
12
87
229-231
[230-232]38
OH
O
O
OH
Cl
O
3e
e
M
HO
C
6.
13
85
209-210
[210-211]38
OH
O
O
e
M
OH
O
3f
123

Trifluoroethanol and liquid-assisted grinding method…
Table 3 continued
Sr.
Salicylaldehydes
Product
Time
(min)
Yielda
M.P.
(oC) [L]b
No.
(%)
O
HO
C
HN
NH
7.
11
86
85
220-221
[220-222]39
O
O
O
H
OH
N
O
N
H
O
3g
O
HO
HO
C
HN
NH
8.
12
232-234
[234-235]39
O
O
O
OH
H
HO
N
O
N
H
O
3h
O
r
B
HO
C
HN
NH
9.
13
85
240-242
[240-241]39
O
O
O
OH
H
r
B
N
O
N
H
O
3i
O
HN
NH
MeO
HO
C
10.
11.
12
14
86
84
> 300
[> 300]39
O
O
O
H
OH
e
M
O
N
O
N
H
O
3j
O
O
HO
C
HN
NH
240-241
[244-245]39
O
O
O
H
OH
N
OH
N
H
O
OH
3k
O
HN
NH
HO
C
12.
12
80
282-284
[282-284]39
O
O
O
H
OH
N
t
OE
O
N
H
O
O
Et
3l
Reaction conditions: salicylaldehydes (1 mmol), dicarbonyl compounds (2 mmol), TFE (0.5 mL)
aIsolated yield
bReference
123

T. Lohar et al.
O
O
R
H
C O
R
N
N
H
TFE LA
/
G
+
N
NH2
H
COO
O
Scheme 3 Synthesis of isoindolo[2,1-a]quinazolines
equally suitable for stearically hindered salicylaldehydes (Table 3, Entries 11 and
12).
With these satisfactory and encouraging results in hand, we extended synthetic
applicability of the TFE-LAG method for one-pot three-component synthesis of
bioactive isoindolo[2,1-a]quinazolines (Scheme 3). The isoindolo[2,1-a]quinazoli-
nes have been synthesized using I2 in ionic liquid [51], Zr (DS)4 in water [52], nano-
CuO powder [53], b-cyclodextrin [54], Baker’s yeast [55], montmorillonite K-10
[56], and acetic acid [57].
In an initial endeavor, we performed the reaction between an equimolar mixture
of 2-aminobenzamide and 2-carboxybenzaldehyde under the TFE-LAG method at
ambient temperature. The progress of the reaction was monitored by TLC. The best
results were obtained when 0.5 mL of TFE was used as catalyst (Table 4).
To have a better understanding of the performance of our catalytic system, the
effectiveness of the TFE-LAG method was also compared to that of catalysts
reported previously. The results are listed in Table 5. Overall, the yields obtained
from the TFE-LAG method are quite close to those from other reported methods.
As excellent results were obtained by the TFE-LAG method, we focused the
scope of this protocol towards the synthesis of different isoindolo[2,1-a]quinazo-
lines by applying various substituted 2-aminobenzamides (Table 6). The reaction
displayed high functional group tolerance and proved to be the best method for the
synthesis of isoindolo[2,1-a]quinazolines. It was observed that 2-aminobenzamide
with methyl and methoxy substituents gave higher yields of the products due to
higher nucleophilicity (Table 6, Entries 3 and 4), whereas halogen substituents offer
slightly lower yield of the corresponding products (Table 6, Entries 5 and 6). The
reactions with electron-withdrawing nitro groups gave slightly lower yields under
the optimized conditions (Table 6, Entries 7 and 8). Sterically hindered
2-aminobenzamides well tolerate the reaction and offer good product yield
(Table 6, Entry 9). Cyclic saturated 2-aminobenzamide offered excellent yield
due to high nucleophilicity (Table 6, Entry 10). Moreover, other substituted
2-aminobenzamides were the most suitable substrates for the reaction (Table 6,
Entries 11 and 12).
As the product is separated from the reaction mixture, workup involves simple
filtration for the isolation of the product (Table 6, Entry 4a), the structure of which
1
was confirmed by spectral techniques such as IR, H NMR, 13C NMR and mass
analysis (see ESM, Figs. 2–5).
123

Trifluoroethanol and liquid-assisted grinding method…
Table 4 Optimization of reaction conditions
Entries
Solvent
Conditions
Time (min)
Yielda (%)
1
2
3
4
TFE
25 °C
80 °C
Grinding
60
80
10
60
60
82
90
20
TFE
TFE
Ethanol
80 °C
Reaction conditions: 2-aminobenzamide (1 mmol), 2-carboxybenzaldehyde (1 mmol), TFE (0.5 mL)
aIsolated yields
Table 5 Reported catalytic systems for the synthesis of isoindolo[2,1-a]quinazolines
Entries
Catalyst
Reaction conditions
Time (min)
Yielda (%)
References
1
2
3
4
5
6
7
8
I2
Ionic liquid/80 °C
Water/RT
60
60
90
90
86
70
84
72
90
90
[51]
Zr (DS)4
[52]
Nano CuO powder
b-cyclodextrin
Baker’s yeast
Montmorillonite K-10
Acetic acid
TFE
Water/reflux
Water/microwave
THF/ultrasound
Ethanol/reflux
110 °C
600
10
[53]
[54]
120
900
45
[55]
[56]
[57]
Grinding
10
This work
Reaction conditions: 2-aminobenzamide (1 mmol), 2-carboxybenzaldehyde (1 mmol)
aIsolated yields
The infrared spectrum of the product depicted a broad signal at 3448 cm-1 for
N–H stretching vibrations of the cyclic amide group, whereas the amide carbonyl
stretching vibrations of the pentacyclic and hexacyclic rings were observed at 1725
and 1678 cm-1, respectively. The weak signals at 2925 and 3061 cm-1 due to C–H
stretching vibrations of the aromatic group were observed. In the 1H NMR
spectrum, a remarkable sharp singlet for methine carbon was observed at d
6.25 ppm. The remaining protons of the aromatic ring resonated between d 7.20 and
d 8.06 ppm. The N–H proton shows a broad peak at d 9.24 ppm. In 13C-NMR
spectrum, characteristic methine carbon in the cyclized product appeared at d
67.5 ppm. All aromatic carbon atoms observed at d 119.9 to 140.6 ppm. Two
carbonyl groups noticed at d 164.3 and 165.0 ppm. The molecular ion peak at m/z
250 (M?) corresponds to the molecular weight of the compound.
123

T. Lohar et al.
Table 6 Synthesis of isoindolo[2,1-a]quinazolines
Sr.
No.
2-aminobenzamides
Product
Time
(min)
Yielda
(%)
MP. (oC)
[L]b
O
N
N
O
1.
N
H
07
90
180-182
[184-185]53
NH2
O
4a
O
N
N
O
2.
3.
08
08
88
91
155-157
[155-157]53
N
H
NH2
O
4b
CH3
C
H
3
O
O
N
N
199-201
[199-200]54
N
H
NH2
O
4c
OCH3
OCH3
4.
O
O
09
91
137-139
[135-137]53
N
N
H
NH2
N
O
4d
Cl
Cl
O
N
O
N
N
H
10
10
86
86
184-185
[186-187]53
5.
6.
NH2
O
4e
r
B
r
B
115-117
[117-119]54
O
N
O
N
N
H
NH2
O
4f
123

Trifluoroethanol and liquid-assisted grinding method…
Table 6 continued
Sr.
No.
2-aminobenzamides
Product
Time
(min)
Yielda
(%)
MP. (oC)
[L]b
NO2
O
N
N
NO2
7.
8.
09
85
235-237
[241-243]57
O
N
H
NH2
O
4g
O
O
N
N
10
86
216-218
[217-219]57
N
O2
N
N
O2
H
NH2
O
4h
O
O
N
N
9.
10
85
166-168
[169-170]54
N
H
NH2
O
4i
O
N
N
O
N
H
NH2
10.
11.
09
07
85
88
151-153
[152-154]53
O
4j
O
O
NH2
NH
N
278-280
NH2
[280-281]51
O
4k
O
O
N
N
C4H9
C4H9
N
H
12.
09
87
139-141
[141-143]51
NH2
O
4l
Reaction conditions: 2-aminobenzamides (1 mmol), 2-carboxybenzaldehyde, (1 mmol), TFE (0.5 mL)
aIsolated yield
bReference
123

T. Lohar et al.
Conclusion
In conclusion, we have developed green and efficient synthesis of chromenes and
isoindolo[2,1-a]quinazolines under the TFE-LAG method. Here, TFE acts as
Brønsted acid and plays a significant role in increasing the electrophilic character of
the aldehyde. The reaction proceeds via Knoevengel condensation followed by
Michael-type addition. The TFE-LAG method brings better results than dry
grinding. In addition to this, the method has notable outcomes such as conversion
under mild reaction conditions and operational simplicity with good yields.
Acknowledgements One of the authors, Mr. Trushant Lohar, is very much grateful to the Department of
Science and Technology (DST) for providing a DST-INSPIRE fellowship (IF-140918).
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