The Remarkable Cooperative Effect of a Br?nsted-Acidic Ionic Liquid in the Cyclization of 2-Aminobenzamides with Ketones

Article abstract of DOI:10.1002/ejoc.201700966

An unprecedented role of an imidazolium Br?nsted acidic ionic liquid was found in the formation of 2,2-disubstituted quinazolin-4(1H)-one derivatives; both the C2-H of the imidazolium moiety and an acidic proton were necessary and simultaneously took part in the catalysis. A library of quinazolin-4(1H)-ones was prepared from readily available ketones and 2-aminobenzamides; excellent yields were obtained through simple crystallization under solvent-free conditions with lower E factors. The catalyst could be reused over five consecutive runs without any significant loss in catalytic activity. This method produces only water as a byproduct and represents a green synthetic protocol. A clean reaction, no chromatographic purification, easily accessible reactants, a metal-free and solvent-free process, and environmentally friendly reaction conditions are the notable advantages of this procedure. The possible role of the C2-H of the imidazolium moiety in catalysis was studied by mass spectrometry.

Full text of DOI:10.1002/ejoc.201700966

A Journal of
Accepted Article
Title: The Remarkable Cooperative Effect of a Brønsted Acidic Ionic
Liquid in Cyclization between 2-Aminobenzamides with Ketones
Authors: Alakananda Hajra, Sudarshan Das, Sougata Santra, Sourav
Jana, Grigory V. Zyryanov, and Adinath Majee
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700966
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10.1002/ejoc.201700966
European Journal of Organic Chemistry
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The Remarkable Cooperative Effect of a Brønsted Acidic Ionic
Liquid in Cyclization between 2-Aminobenzamides with Ketones
Sudarshan Das,[a] Sougata Santra,[b] Sourav Jana,[a] Grigory V. Zyryanov,[b,c] Adinath Majee,[a] and
Alakananda Hajra*[a]
Abstract: An unprecedented role of an imidazolium Brønsted acidic
ionic liquid has been found in the formation of 2,2-disubstituted
quinazolin-4(1H)-one derivatives where both C2-H of imidazolium
moiety and acidic proton are necessary and simultaneously take part
in catalysis. A library of quinazolin-4(1H)-ones was prepared from
readily available ketones and 2-aminobenzamides in excellent yields
through simple crystallization under solvent-free conditions with
lower E factor. The catalyst can be reused for five consecutive runs
without any significant loss of catalytic activities. This method
produced only water as the byproduct and represents a green
synthetic protocol. Clean reaction, non-chromatographic purification
technique, easily accessible reactants, metal and solvent-free and
environmentally friendly reaction conditions are the notable
advantages of this procedure. The possible role of C2-H of
imidazolium moiety in catalysis was studied by mass spectrometry.
in the field of catalysis.6 BAILs are more preferable over the
mineral acids as BAILs show strong acidity with usual properties
of ionic liquids. As a result many transformations have been
carried out involving acidic proton of these ILs.[6] However the
specific role of cationic imidazole moiety with a pendant acidic
sulfonic acid functionality has not been studied systematically.[7]
During the last few years we are actively engaged in the
field of catalysis using BAILs as well as imidazole based
zwitterions.[8] It is known that imidazolium motif provides an
unconventional C–H bond for bonding.[9] Our previous study
proves that C2-H of the imidazole moiety also plays a crucial
role in catalyzing the reaction via electrophilic activations.[8e,f] In
this regard, aldehydes are easily activated through the formation
of hydrogen bond between the C2-H of imidazolium moiety and
carbonyl oxygen atom of aldehyde. But this electrophilic
activation is not sufficient to activate the ketones to react with
nucleophiles and probably for this reason ketone has not been
investigated as reaction partner catalyzed by imidazolium based
ionic liquid under the guidance of hydrogen bonding. We
therefore became interested to design such an ionic liquid which
could serve as a Brønsted acid catalyst where both imidazolium
C2-H and acidic proton could co-operatively activate ketone. In
order to test this hypothesis, we applied 1-butanesulfonicacid-3-
methylimidazolium tosylate [BSMIm][OTs] as a catalyst for the
synthesis of 2,2-disubstituted quinazolin-4(1H)-one derivatives
from ketones.
Introduction
Room-temperature ionic liquids (RTILs) have been explored as
greener alternatives to the volatile organic solvents due to their
unique properties, such as negligible vapor pressure, high
thermal stability, large liquid temperature range, easy
recyclability, excellent chemical stability, and strong dissolving
power for a wide range of organic and inorganic molecules.[1]
However, their uses in large quantities as solvents are
associated
with
limitations
such
as
combustibility,
biodegradability, toxicity, and high cost.[2] As a consequence,
now a days ionic liquids have been used as effective catalysts
rather than only as media for organic transformations.[3] By
changing the cations and/or anions, the properties of ILs can be
turned into many different ways. So far, a large number of
functionalized ILs have been prepared for different applications
by choosing the appropriate cations and anions.[4]
After the report by Forbes and Davis for the synthesis of
the new class of phosphonium- and imidazolium ion-based ILs
equipped with a pendant acidic sulfonic acid moiety,[5] Brønsted
acidic ionic liquids (BAILs) have drawn a considerable attention
Figure 1. Quinazolinone containing drugs.
[a]
Dr. S. Das, Mr. S. Jana, Dr. A. Majee, Dr. A. Hajra
Department of Chemistry, Visva-Bharati (A Central University),
Santiniketan-731235, India.
E-mail: alakananda.hajra@visva-bharati.ac.in
http://vbchem.ac.in/AlakanandaHajra/
Dr. S. Santra, Prof. Dr. G. V. Zyryanov
Department of Organic and Biomolecular Chemistry
Chemical Engineering Institute, Ural Federal University
19 Mira Str., Yekaterinburg, 620002, Russian Federation
Prof. Dr. G. V. Zyryanov
I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the
Russian Academy of Sciences, 22 S. Kovalevskoy Str.,
Yekaterinburg, 620219, Russian Federation
Quinazolinone and its derivatives are ubiquitous in many
natural products such as vitamins, alkaloids and are also found
to be as antagonists of various biological receptors, such as 5-
HT5A related diseases, calcitonin gene-related peptide, and
vasopressin V3 receptors.[10] Quinazolinone scaffolds have also
been used for designing various commercially available drugs
such as Fenquizone (used in the treatment of oedema and
hypertension), Quinethazone (used to treat hypertension),
Iressa (clinically used against cell lung cancer with ever
increasing popularity) and Doxazosin (used as antihypertensive
[b]
[c]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700966
European Journal of Organic Chemistry
FULL PAPER
agent) (Figure 1).[11] Although several methods are available in
literature for the synthesis of 2-arylquinazolinones,[12] only few
methods are available for the synthesis of 2,2-disubstituted
quinazolin-4(1H)-one derivatives.[13] However these methods
were carried out in organic solvents using different catalysts. To
the best of our knowledge, there is no report available so far for
the synthesis of 2,2-disubstituted quinazolin-4(1H)-one
derivatives by using the functionalized ionic liquid as a catalyst.
As a part of our ongoing program on catalysis by IL,[8] herein we
report a remarkable cooperative effect of both the acidic proton
and the C2-H of the imidazole moiety on the cyclization reaction
between 2-aminobenzamides and ketones for the formation of
2,2-disubstituted quinazolin-4(1H)-ones (Scheme 1).
by carrying out the reactions with [DMImB][OTs] (E) and
[BDMIm][SO3H] (H) (where C2-H is substituted by methyl group).
But no formation of desired product was observed (entries 6 &
11, Table 1) which suggests the significant catalytic effect of C2-
H on this reaction. These results strongly support that the
reaction is influenced by both SO3H and C2-H of imidazolium
moiety. It is noteworthy to mention that the reaction did not
proceed in the presence of acidic catalysts such as HCl, AcOH,
TFA, TfOH and NaHSO3 (Table 2). Furthermore, these results
indicate that the presence of acidic proton is not the only factor
to catalyze the reaction.
With the optimized reaction conditions (entry 1, table 1) in
hand, we turned our attention towards examining the substrates
scope with respect to ketones and the results are summarized in
Table 3. Aliphatic ketones such as acetone and 4-methylpentan-
2-one underwent the cyclization reaction smoothly to give the
desired products in excellent yields (3a & 3b). Aromatic ketones
also afforded the corresponding products with excellent yields
(3c-3n). Aryl ketones such as acetophenone and propiophenone
reacted well under the present reaction conditions (3c & 3d).
Benzophenone also afforded the desired product (3e) with high
yield in comparison to
a
previously reported method.13a
Acetophenones bearing electron-donating groups such as –Me
and –SMe and electron withdrawing groups like –Cl and –Br
produced the desired products without any difficulty. Free
hydroxy group on phenyl moiety in acetophenone also afforded
the corresponding product (3i) with high yield. Acetophenone
with strong electron-withdrawing group –CF3 reacted well (3k).
Hetero-aryl ketones afforded the desired products with excellent
yields (3l-3n) without accompanying self-condensation or ring
cleavage.
Scheme 1. BAIL-catalyzed cyclization between 2-aminobenzamides and
ketones.
Results and Discussion
To study the factors which govern the catalytic activity of the IL
in this reaction, we selected 2-aminobenzamide and acetone as
model substrates employing various structurally diversified
imidazolium based ILs, zwitterionic salt and BAILs. The
reactions were carried out at room temperature and the results
are summarized in Table 1. It made a clear distinction among
various acidic ILs as catalysts in this reaction. Initially, we tested
[BSMIm][OTs] (A) as a catalyst for the model reaction and
gratifyingly 98% of the desired product was obtained within 5
min (entry 1, table 1). In the absence of catalyst no product was
detected, even after 24 hour (entry 2, table 1). Another acidic IL
[BSMIm][OTf] (B) gave the similar result with 96% yield (entry 3,
Table 1). Chain length has significant role in controlling the
reaction. When the chain length of IL was decreased the yield of
the product decreased (entry 1 vs 4, Table 1). However, other
ILs such as [PMIm][Br] (D) was found ineffective for this
transformation (entry 5, table 1). This result implies that SO3H
group (acid) plays a crucial role in this reaction. In the presence
of either only para-toluene sulfonic acid (PTSA) or the
combination of PTSA and IL (entries 7 & 8, Table 1), no desired
product was obtained within 5 min at room temperature. Aprotic
imidazolium zwitterion (F) and imidazole could not catalyze the
reaction also (entries 9 & 15, Table 1). The reactions did not
proceed at all in the presence of ILs bearing counter anions
SO3H- (G) (entry 10, table 1) and TsO- (I) (entry 12, Table 1)
without having pendant acidic SO3H group on imidazolium part.
No desired product was obtained when we used the combination
of I with either HCl (entry 13, Table 1) or PTSA (entry 14, Table
1). Next we checked the effect of C2-H of the imidazole moiety
Table 1 Effects of different ILs as catalyst[a]
Entry
1
Catalysts
Time
5 min
Yields[b] (%)
98
2
3
None
24 h
0
5 min
96
4
5
5 min
5 min
84
0
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10.1002/ejoc.201700966
European Journal of Organic Chemistry
FULL PAPER
O
O
6
5 min
0
O
A
BAIL (5 mol %)
NH
NH2
+
R1
N
R1
R2
RT
NH2
R2
H
2
1a
3
7
8
PTSA
5 min
5 min
0
0
O
O
O
O
NH
NH
NH
NH
N
H
N
H
N
H
N
H
3c, 15 min, 92%
3b, 10 min, 94%
3a, 5 min, 98%
3d
, 5 min, 98%
O
O
O
O
Br
9
5 min
0
NH
NH
NH
NH
Cl
N
H
N
H
N
H
N
H
3f
3g
3h
, 15 min, 92%
, 10 min, 95%
, 10 min, 90%
10
11
5 min
5 min
0
0
3e, 20 min, 88%
O
O
O
NH
NH
NH
OH
SMe
CF3
N
H
N
H
N
H
3i
3k
, 25 min, 88%
, 10 min, 92%
O
3j, 25 min, 92%
O
O
Br
12
13
5 min
5 min
0
0
NH
S
NH
S
NH
N
H
N
N
N
H
H
3n, 20 min, 92%
3m, 15 min, 94%
3l
, 15 min, 93%
[a] 1a (1 mmol) was reacted with 2 (1 mmol) in the presence of BAIL A (5
mol %) at rt. All are isolated yields.
14
15
5 min
5 min
0
0
Recently spiroheterocyclic compounds present in many
natural products and have attracted considerable interest in
medicinal and pharmaceutical chemistry due to their unique
structural array and highly pronounced pharmacological
activities.[14] By virtue of our method various spiroquinazolin-4-
(1H)-one derivatives were synthesized with high yields (Table 4).
In addition, spiroheterocyclic quinazolin-4-(1H)-one derivatives
were also obtained in excellent yields (3q-3s). Ethyl 4-
oxopiperidine-1-carboxylate also reacted smoothly to afford the
corresponding spiroheterocyclic quinazolin-4-(1H)-one derivative
(3s).
Imidazole
[a] 1a (1 mmol) was treated with 2a (1 mmol) in the presence of different
catalysts (5 mol%) under neat condition at rt. [b] Isolated yields.
Table 2 Effects of different acidic catalysts[a]
Entry
Catalyst (5 mol %)
HCl (12 N)
CH3COOH
CF3COOH
TfOH
Time
5 min
5 min
5 min
5 min
4 h
Yield[b] (%)
1
2
3
4
5
6
0
0
Table 4 Synthesis of spiroheterocyclic quinazolin-4-(1H)-ones[a]
0
O
O
O
O
NH
NH
NH
NH
0
N
H
N
H
N
H
N
H
O
S
PTSA
<10
0
3r
, 40 min, 88%
3o, 10 min, 94%
3q, 40 min, 87%
3p
, 15 min, 93%
O
NaHSO3
6 h
O
NH
N
[a] 1a (1 mmol) was treated with 2a (1 mmol) in the presence of different
catalyst (5 mol %) under neat condition at rt. [b] Isolated yields.
NH
N
OEt
H
N
H
O
3t
, 50 min, 89%
3s
, 30 min, 92%
Table 3. Substrates scope a
[a] 1a (1 mmol) was reacted with 2 (1 mmol) in the presence of BAIL A (5
mol %) at rt. All are isolated yields.
To further explore the scope of 2-aminobenzamide
derivatives, N-substituted 2-aminobenzamides were investigated
as depicted in Scheme 2. The desired products were obtained in
high yields (3u-3v).
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0.073 g
(96.1%)
98%
(3.27 g)
1
2
3
4
19
18
17
16
0.076
0.073
0.070
0.067
0.070 g
(95.8%)
97%
(3.07 g)
0.067 g
(95.7%)
97%
(2.90g)
0.064 g
(95.5%)
96%
(2.70 g)
Scheme 2. Synthesis of 2,2,3-trisubstituted quinazolinone derivatives.
[a] Reactions were carried out with 1a (1 equiv) and 2a (1 equiv) in the
presence of BAIL A (5 mol %) at rt for 5 min. All reactions were carried out in
same reaction vessel. [b] Isolated yields.
In the light of green chemistry, the concept of environmental
factor (E-factor) and atom economy have been incorporated in
conventional organic synthesis in both industry and academia.[15]
Solvents are the main reason for an insufficient E-factor,
especially in synthesis of fine chemicals and pharmaceutical
industries. A greener reaction condition has been developed
bearing lower E-factor of 0.12 and 0.16 in the cases of
synthesizing 3a and 3o respectively (see Supporting
Information).
This methodology is also applicable on a gram-scale
synthesis (Scheme 3). We have successfully prepared the
quinazolinone 3a in 99% yield by the cyclization of 2-
aminobenzamide (1a, 20 mmol) and acetone (2a, 20 mmol)
using 5 mol% BAIL A.
A plausible mechanism for the synthesis of quinazolin-4-
(1H)-one is depicted in Scheme 4. The crucial and distinct effect
of BAIL on the overall reaction can be envisaged through
domino catalysis involving an initial electrophilic activation of
carbonyl oxygen of ketone through H-bond formation with SO3H
group. The additional H-bond involving the amidic carbonyl
oxygen with the imidazolium C2-H[3c,d,16] further brings the
reacting partners in close proximity favoring the formation of H-
bonded supramolecular assembly.[16] The H-Bond interaction as
well as charge-charge interaction cooperatively assist to form
supramolecular assembly (I). Nucleophilic attack by amine at
carbonyl carbon of ketone followed by dehydration gives the
intermediate (II). The intermediate (II) also undergoes
electrophilic-nucleophilic dual activation[4d] with the IL which
facilitates intramolecular cyclization at this stage to afford the
final product 3. Mass spectrometry-based ion-fishing technique
has appeared as vital tool in understanding mechanistic course
of organic reactions.[3d,16c,17] Therefore, to identify the clusters
and/or reactive intermediates (RI), the mass spectrometric ESI
(+ve) ion-fishing studies have been carreid out (see Supporting
Information). In a representative example, 2-aminobenzamide
was treated with 4-chloroacetophenone in the presence of
catalytic amount of A (5 mol%) and after 5 min the reaction
mixture was subjected to the (+ve) ESI-MS analysis (see
Supporting Information). Several peaks have appeared in the
total ion chromatogram (TIC) spectra (see Supporting
Information) which revealed the presence of ions at m/z 703.40
(m1), 653.33 (m2), 543.50 (m3), 529.48 (m4), 515.45 (m5), 501.44
(m6) and 459.17 (m7) corresponding to [RI-I + Na]+ (m1), [m1 - Cl
Scheme 3. Gram-scale synthesis.
The reusability of the catalyst is also important from the
viewpoint of commercial applications. Therefore the recovery
and reusability of the catalyst were investigated for synthesis of
3a (Table 5). The recovered catalyst can be recycled
successfully without significant loss of catalytic activity. After
third cycle, the catalyst still had a high activity and gave the
desired product in excellent yield (96%).
Table 5 Recycling of the BAIL A for synthesis of 3a[a]
.
- CH3] (m2), [(RI-I + H + H+) - ClC6H4CO] (m3), [(m3 + H)+ - CH3]
(m4), [(m4 + H)+ - CH3] (m5), [(m5 + H)+ - CH3] (m6), and [(m6 + H. +
H)+ - CONH2] (m7) respectively, which suggests the formation of
RI-I. The peaks at m/z 619.00, 567.34 and 551.17 correspond to
[RI–II + H+ - CONH2], [RI–II + H+ - CH2SO3H] and [RI–II + H+ -
C6H4Cl] suggesting the formation of RI-II.
Amount
the BAIL (A)
used (g)
of
BAIL (A)
recovery
Use/Cycle
Fresh
Scale/mmol
20
Yieldb
0.076 g
(97.4%)
99%
(3.48 g)
0.078
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10.1002/ejoc.201700966
European Journal of Organic Chemistry
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Scheme 4. Plausible reaction pathway.
General procedure for the synthesis of 2,2-disubstituted quinazolin-
4(1H)-one.
Conclusions
5 Mol% of BAIL (A) was added to a mixture of 2-aminobenzamide 1 (1
mmol) and ketone 2 (1 mmol) and the reaction mixture was stirred at
room temperature for a certain period of time as indicated by TLC. After
completion of the reaction, little amount of water (5 mL) was added to the
reaction mixture and the crude product was isolated as solid by filtration.
To get the analytically pure product, the solid was crystallized from
ethanol. The catalyst left in the reaction vessel was dried by evaporating
water under rotary vacuum evaporator and employed for subsequent four
consecutive runs without significant loss of catalytic activity.
In summary, we have demonstrated an unprecedented catalytic
activity of an imidazolium based Brønsted acidic ionic liquid
(BAIL) for the synthesis of 2,2-disubstituted quinazolin-4(1H)-
one derivatives by the reaction of ketones with 2-
aminobenzamides with excellent yields at room temperature
under solvent-free conditions. To the best of our knowledge, this
is the first report of activation of ketone for electrophilic addition
by a BAIL where both C2-H and acidic-H are necessary. Our
findings clearly demonstrate the necessity of C2-H of
imidazolium cation and acidic proton for the activation of ketone.
The notable advantages of the present methodology are clean
reaction, ease of product isolation/purification (no need to use
column chromatography), easily accessible reactants, metal and
solvent-free and environmentally friendly reaction conditions and
water is the only byproduct. The mass spectrometry studies
support the formation of the supramolecular assembly from the
interaction with amide, BAIL and ketone through H-bond
formation. We hope that our new findings will be beneficial in the
field of catalysis by IL.
2,3-Dihydro-2,2-dimethylquinazolin-4(1H)-one (3a):[10c] White solid
(172 mg, 98% yield); Mp 182-183 °C (Lit.[10c] 182-183 °C); IR (KBr): 1614,
1642, 3263, 3334 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.37 (s, 6H),
6.60-6.65 (m, 3H), 7.21 (t, J = 8.4 Hz, 1H ), 7.57 (d, J = 8.0 Hz, 1H), 7.94
(br s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 29.0, 66.8, 113.8, 114.2,
116.2, 127.1, 133.2, 147.0, 163.0.
2,3-Dihydro-2-(iso-butyl)-2-methylquinazolin-4(1H)-one
(3b):[10c]
White solid (204 mg, 94% yield); Mp 170-172 °C (Lit.[10c] 171-173 °C); IR
(KBr): 1612, 1641, 3172, 3326 cm-1; 1H NMR (400 MHz, DMSO-d6): δ
0.86-0.90 (m, 6H ), 1.34 (s, 3H), 1.52-1.54 (m, 2H), 1.83-1.86 (m, 1H),
6.56-6.62 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.87
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 23.3, 24.2, 24.4, 28.6, 49.3,
69.3, 113.3, 113.9, 116.0, 127.0, 133.2, 147.1, 163.0.
Experimental Section
2,3-Dihydro-2-methyl-2-phenylquinazolin-4(1H)-one (3c):[10c] White
solid (218 mg, 92% yield); Mp 223-225 °C (Lit.10c: 224-225 °C); IR (KBr):
1615, 1671, 3047, 3404 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.65 (s,
3H), 6.58 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 7.16-7.22 (m, 2H),
7.28 (t, J = 8.4 Hz, 2H), 7.50-7.52 (m, 3H), 7.65 (br, s, 1H), 8.81 (br s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 30.7, 70.1, 114.3, 115.0, 116.8,
125.1, 127.0, 127.2, 127.9, 133.3, 147.2, 147.6, 163.8.
Materials and methods
1H NMR spectra were determined on
a Bruker 400 (400 MHz)
spectrometer as solutions in DMSO-d6. Chemical shifts are expressed in
parts per million (δ) and are referenced to tetramethylsilane (TMS) as
internal standard and the signals were reported as s (singlet), d (doublet),
t (triplet), m (multiplet) and coupling constants J were given in Hz. 13C
NMR spectra were recorded at 100 MHz in DMSO-d6 solution. TLC was
done on silica gel coated glass slide (Merck, Silica gel G for TLC).
Melting points were determined on a glass disk with an electric hot plate
and are uncorrected. All solvents were dried and distilled before use.
Commercially available substrates were freshly distilled before the
reaction. Solvents, reagents and chemicals were purchased from Aldrich,
Fluka, Merck, SRL, Spectrochem and Process Chemicals. All reactions
involving moisture sensitive reactants were executed using oven dried
glassware.
2,3-Dihydro-2-ethyl-2-phenyl-quinazolin-4(1H)-one (3d): White solid
(246 mg, 98% yield); Mp 238-240 °C; IR (KBr): 1608, 1650, 3193, 3319
cm-1; 1H NMR ( 400 MHz, DMSO-d6 ): δ 0.99 (t, J = 7.2 Hz, 3H), 1.83 (q,
J = 7.2 Hz, 2H), 6.56 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0Hz, 1H), 7.15-
7.22 (m, 2H), 7.28 (t, J = 8.0 Hz, 2H), 7.47-7.50 (m, 4H), 8.69 (s, 1H); 13
C
NMR (100 MHz, DMSO-d6): δ 8.6, 35.0, 73.2, 114.1, 114.7, 116.5, 125.4,
126.9, 127.2, 127.9, 133.2, 147.5, 147.7, 164.2. Anal. Calcd for
C16H16N2O: C, 76.16; H, 6.39; N, 11.10%; Found: C, 76.12; H, 6.31; N,
11.03%.
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10.1002/ejoc.201700966
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2,2-Diphenyl-2,3-dihydroquinazolin-4(1H)-one (3e):[10a] White solid
(264 mg, 88% yield); White solid; Mp 139-141 °C (Lit.[10a] 138-142 °C); IR
(KBr): 1612, 1648, 3187, 3321 cm-1; 1H NMR (400 MHz, DMSO-d6 ): δ
6.59-6.60 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 7.21-7.25 (m, 1H), 7.30-7.37
(m, 6H), 7.43 (d, J = 7.2 Hz, 4H), 7.51 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H),
8.98 (s, 1H); 13C NMR (100 MHz, DMSO-d6 ): δ 75.4, 114.6, 114.8, 117.1,
127.2, 127.5, 127.8, 133.4, 144.7, 147.0, 163.7.
2,3-Dihydro-2-methyl-2-pyridin-2-yl quinazolin-4(1H)-one (3l): White
solid (222 mg, 93% yield); Mp 242-244 °C; IR (KBr): 1616, 1654, 3201,
3265 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.66 (s, 3H) , 6.57 (t, J = 7.2
Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 7.15-7.24 (m, 2H), 7.49 (d, J = 8.0 Hz,
3H), 7.75 (t, J = 7.6 Hz, 1H), 852 (s, 1H), 8.63 (s, 1H); 13C NMR (100
MHz, DMSO-d6): δ 28.8, 71.0, 114.4, 114.6, 116.9, 119.4, 122.5, 127.1,
133.2, 136.7, 147.2, 148.7, 163.7, 164.5. Anal. Calcd for C14H13N3O: C,
70.28; H, 5.48; N, 17.56%; Found: C, 70.22; H, 5.40; N, 17.48%.
2,3-Dihydro-2-(4-chlorophenyl)-2-methylquinazolin-4(1H)-one
(3f):[10c] White solid (258 mg, 95% yield); Mp 209-211 °C (Lit.[10c] 210-
212 °C); IR (KBr): 1611, 1637, 3030, 3244 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ 1.63 (s, 3H), 6.57-6.76 (m, 1H), 6.77 (d, J = 8 Hz, 1H),
7.19-7.23 (m, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.48-7.51 (m, 3H), 7.67 (s,
1H), 8.83 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 30.4, 69.8, 114.3,
115.0, 117.0, 127.1, 127.2, 127.9, 131.8, 133.4, 146.7, 146.9, 163.7.
2,3-Dihydro-2-methyl-2-thiophen-2-yl-quinazolin-4(1H)-one
(3m):
White solid (229 mg, 94% yield); Mp 208-210 °C; IR (KBr): 1614, 1633,
3201, 3234 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.78 (s, 3H), 6.64 (t,
J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.00-
7.01 (m, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 7.53-7.57
(m, 2H), 8.77 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 30.8, 68.6, 114.4,
114.6, 117.2, 123.8, 124.7, 126.6, 127.2, 133.4, 146.7, 153.0, 163.4.
Anal. Calcd. for C13H12N2OS: C, 63.91; H, 4.95; N, 11.47%; Found: C,
63.83; H, 4.87; N, 11.41%.
2,3-Dihydro-2-methyl-2-p-tolylquinazolin-4(1H)-one (3g):[10c] White
solid (226 mg, 90% yield); Mp 219-221 °C (Lit.[10c] 218-220 °C); IR (KBr):
1639, 3028, 3255 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.61 (s, 3H),
2.20 (s, 3H), 6.58 (t, J = 7.2 Hz,, 1H), 6.75 (d, J = 8.0 Hz, 1H), 7.07 (d, J
= 8.0 Hz, 2H), 7.17-7.21 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.74 (d, J =
8.0 Hz, J = 1.2 Hz, 1H), 7.58 (s, 1H), 8.72(s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 20.4, 30.7, 70.0, 114.2, 115.0, 116.7, 125.1, 127.2, 128.4,
133.2, 136.1, 144.7, 147.2, 163.8.
2,3-Dihydro-2-(5-bromo-thiophen-2-yl)-2-methylquinazolin-4(1H)-one
(3n): White solid (296 mg, 92% yield); Mp 252-254 °C; IR (KBr): 1577,
1614, 3161, 3236 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.76 (s, 3H),
6.68 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H),
6.99 (d, J = 4.0 Hz, 1H), 7.23-7.25 (m, 1H), 7.57-7.59 (m, 2H), 8.82 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 30.3, 68.6, 109.7, 114.6, 114.7,
117.7, 124.7, 127.3, 130.0, 133.6, 146.5, 154.9, 163.4. Anal. Calcd for
C13H11BrN2OS: C, 48.31; H, 3.43; N, 8.67%; Found: C, 48.25; H, 3.35; N,
8.61%.
2-(3-bromophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one
(3h):[10c] White solid (290 mg, 92% yield); Mp 201-203 °C (Lit.[10c] 199-
201 °C); IR (KBr): 1607, 1642, 3198, 3312 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ 1.63 (s, 3H), 6.61 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz,
1H), 7.21-7.29 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H),
7.70 (d, J = 7.6 Hz, 2H), 8.84 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ
30.5, 69.9, 114.3, 114.9, 117.1, 121.7, 124.2, 127.3, 128.1, 130.0, 130.2,
133.5, 146.8, 150.6, 163.7.
1',3'-Dihydrospiro[cyclopentane-1,2'-quinazolin]-4'-one
(3o):[10c]
White solid (198 mg, 94% yield); Mp 265-267 °C (Lit.[10c] 265-267 °C); IR
(KBr): 1616, 1639, 3163, 3292 cm-1; 1H NMR (400 MHz, DMSO-d6): 1.64-
1.68 (m, 4 H), 1.77-1.79 (m, 4H), 6.63 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0
Hz, 1H), 6.74 (s, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H),
8.10 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 22.4, 77.5, 114.8, 115.0,
117.0, 127.7, 133.4, 147.9, 163.9.
2,3-Dihydro-2-(4-hydroxyphenyl)-2-methylquinazolin-4(1H)-one (3i):
White solid (223 mg, 88% yield); Mp 278-280 °C; IR (KBr): 1613, 1652,
3173, 3339 cm-1; 1H NMR (400 MHz, DMSO-d6) : δ 1.59 (s, 3H), 6.56 (t,
J = 7.6 Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 7.18 (t,
J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.46-7.48 (m, 2H), 8.62 (s, 1H),
9.31 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 30.8, 69.9, 114.2, 114.5,
114.9, 116.6, 126.3, 127.1, 133.2, 137.8, 147.2, 156.3, 163.8. Anal.
Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02%; Found: C, 70.76; H,
5.50; N, 11.01%.
1',3'-Dihydrospiro[cyclohexane-1,2'-quinazolin]-4'-one (3p):[10c] White
solid (200 mg, 93% yield); Mp 222-224 °C (Lit.[10c] 221-223 °C); IR (KBr):
1614, 1643, 3183, 3286 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.21-
1.27 (m, 1H), 1.40-1.44 (m, 1H), 1.54-1.64 (m, 6 H), 1.73-1.76 (m, 2H),
6.61 (t, J = 7.6 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H),
7.57 (d, J = 8.8 Hz, 1H), 7.94 (, 1H); 13C NMR (100 MHz, DMSO-d6): δ
20.8, 24.6, 37.1, 67.8, 14.4, 114.5, 116.4, 127.1, 133.1, 146.7, 163.2.
2,3-Dihydro-2-methyl-2-(4-methylsulfanyl-phenyl)quinazolin-4(1H)-
one (3j): White solid (261 mg, 92% yield); Mp 244-246 °C; IR (KBr): 1610,
1618, 3191, 3224 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.63 (s, 3H),
2.40 (s, 3H), 6.58 (t, J = 7.2 Hz, 1H), 6.7 (d, J = 8.0 Hz, 1H), 7.16-7.22 (m,
3H), 7.41 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.62 (s, 1H), 8.76
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 14.5, 30.5, 69.9, 114.3, 115.0,
116.9, 125.5, 125.8, 127.2, 133.3, 136.9, 144.3, 147.1, 163.9. Anal.
Calcd for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85%; Found: C, 67.52; H,
5.61; N, 9.78%.
1',3'-Dihydrospiro[tetrahydropyran-4,2'-quinazolin]-4'-one
(3q):[10c]
White solid (189 mg, 87% yield); Mp 231-233 °C (Lit.[10c] 233-235 °C); IR
(KBr): 1612, 1655, 2943, 3314 cm-1; 1H NMR (400 MHz, DMSO-d6): δ
1.73-1.83 (m, 4H), 3.64-3.69 (m, 4H), 6.65, (t, J = 7.6 Hz, 1H), 6.79-6.84
(m, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H);
13C NMR (100 MHz, DMSO-d6): δ 37.6, 62.5, 65.5, 114.5, 114.7, 116.9,
127.2, 133.3, 146.4, 163.2.
1',3'-Dihydrospiro[tetrahydrothiopyran-4,2'-quinazolin]-4'-one
(3r):[10c] White solid (205 mg, 88% yield); Mp 236-238 °C (Lit.[10c] 237-
238 °C); IR (KBr): 1606, 1660, 2936, 3359 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ 1.87-1.93 (m, 2H), 2.03-2.08 (m, 2H), 2.60-2.65 (m, 2H),
2.77-2.84 (m, 2H), 6.64 (t, J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.81 (d, J = 8.0
Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H);
13C NMR (100 MHz, DMSO-d6): δ δ 23.2, 38.3, 66.9, 114.2, 114.6, 116.8,
127.1, 133.3, 146.2, 162.9.
2,3-Dihydro-2-methyl-2-(4-trifluoromethyl-phenyl)quinazolin-4(1H)-
one (3k): White solid (281 mg, 92% yield); Mp 252-254 °C; IR (KBr):
1616, 3226, 3247 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.65 (s, 3H),
6.60 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H),
7.48 (d, J = 7.6 Hz, 1H), 7.70 (s, 4H), 7.79 (s, 1H), 8.93 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 30.2, 70.0, 114.4, 114.9, 117.2, 124.1 (q, J1
=
271 Hz), 125.1 (q, J3 = 4.0 Hz), 125.2, 126.0, 127.3, 127.8 (q, J2 = 31
Hz), 133.5, 146.9, 152.4, 163.7. Anal. Calcd for C16H13F3N2O: C, 62.74;
H, 4.28; N, 9.15%; Found: C, 62.64; H, 4.22; N, 9.11%.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700966
European Journal of Organic Chemistry
FULL PAPER
1',3'-Dihydrospiro[(1-(ethoxycarbonyl)piperidine)-4,2'-quinazolin]-4'-
one (3s):[10c] White solid (265 mg, 92% yield); Mp 216-218 °C (Lit.[10c]
217-219 °C); IR (KBr): 1620, 1656, 2938, 3293 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ 1.17 (t, J = 7.2 Hz, 3H), 1.73 (s, 4H), 3.38-3.42 (m, 2H),
3.57-3.61 (m, 2H), 4. 03 (q, J = 7.2 Hz, 2H), 6.66 (t, J = 8.0 Hz, 1H), 6.79
(t, J =8.0 Hz, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 8.13
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 14.6, 36.5, 60.7, 66.5, 114.3,
114.7, 117.0, 127.2, 133.4, 146.4, 154.6, 163.2.
K. Chakraborti, S. R. Roy, D. Kumar, P. Chopra, Green Chem.
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1',3'-Dihydrospiro[indan-1,2'-quinazolin]-4'-one (3t):[10c] White solid
(222 mg, 89% yield); Mp 224-226 °C (Lit.[10c] 222-223 °C); IR (KBr): 751,
1109, 1154, 1283, 1379, 1420, 1483, 1516, 1617, 1682, 2890, 2952,
3263, 3365 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 2.31-2.40 (m, 2H),
2.96 (t, J = 6.8 Hz, 2H), 6.66-6.71 (m, 2H), 7.14 (s, 1H), 7.16-7.19 (m,
1H), 7.23-7.31 (m, 4H), 7.66 (d, J = 6.8 Hz, 1H), 8.40 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): 27.7, 41.0, 78.5, 114.1, 114.2, 116.8, 122.4, 125.1,
126.7, 127.1, 128.8, 133.4, 141.5, 146.1, 146.9, 163.0.
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(3u): White solid (244 mg, 92% yield); Mp 158-160 °C; IR (KBr): 1581,
1621, 2983, 3267 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 1.35 (s, 6H),
3.34 (s, 3H), 6.69-6.75 (m, 2H ), 6.95 (s, 1H), 7.08 (d, J = 7.6 Hz, 2H),
7.22-7.32 (m, 3H), 7.64 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-
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165 °C); IR (KBr): 1582, 1622, 2986, 3263 cm-1; 1H NMR (400 MHz,
DMSO-d6): δ 1.35 (s, 6H), 3.78 (s, 3H), 6.74 (t, J = 8.4 Hz, 2H ), 6.96 (d,
J = 8.8 Hz, 3H), 7.11 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 6.4 Hz, 1H), 7.63 (d,
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Acknowledgements
A. Hajra acknowledges the financial support from DST, GoWB
(Grant no. 700(Sanc.)/ST/P/S&T/4G-2/2014). S. Santra is
thankful to the Russian Science Foundation – Russia (Ref. # 16-
43-02020) for funding. We are also thankful to DST-FIST and
UGC-SAP.
Synthesis 2016, 48, 4009; k) A. K. Bagdi, D. Kundu, A. Majee,
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Keywords: Brønsted acidic ionic liquid • quinazolin-4(1H)-ones •
solvent-free • lower E-factor • non-chromatographic purification •
mass spectrometric study
G. V. Zyryanov, A. Hajra, A. Majee, Green Chem. 2017
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Accepted manuscript, doi.org/10.1039/C7GC01158J.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700966
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201700966
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Layout 2:
Ionic liquid-catalysis
FULL PAPER
Sudarshan Das, Sougata Santra,
Sourav Jana, Grigory V. Zyryanov,
Adinath Majee, and Alakananda Hajra*
Page No. – Page No.
The Remarkable Cooperative Effect of
a Brønsted Acidic Ionic Liquid in
Cyclization between 2-
Text for Table of Contents
Aminobenzamides with Ketones
An unprecedented role of an imidazolium Brønsted acidic ionic liquid has been found in the formation of 2,2-disubstituted quinazolin-
4(1H)-one derivatives where both C2-H of imidazolium moiety and acidic proton are necessary and simultaneously take part in
catalysis.
This article is protected by copyright. All rights reserved.