Expeditious synthesis of 2,3-dihydroquinazolin-4(1H)-ones in aqueous medium using thiamine hydrochloride (VB1) as a mild, efficient, and reusable organocatalyst

Article abstract of DOI:10.1080/00397911.2017.1337149

A simple and straightforward synthesis of 2,3-dihydroquinazolin-4(1H)-ones is developed by reacting anthranilamide with various aldehydes or ketones under mild reaction conditions, using thiamine hydrochloride as a cost-effective, readily available, and green catalyst in water. Simple purification process, high yields within short reaction time, wide substrate scope, operational simplicity, and reusability of the catalyst up to three cycles enrich the applicability of the protocol.

Full text of DOI:10.1080/00397911.2017.1337149

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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An Expeditious Synthesis of 2,3-
dihydroquinazolin-4(1H)-ones in Aqueous Medium
Using Thiamine Hydrochloride (VB1) as a Mild,
Efficient and Reusable Organocatalyst
Jutika Devi, Subarna Jyoti Kalita & Dibakar Chandra Deka
To cite this article: Jutika Devi, Subarna Jyoti Kalita & Dibakar Chandra Deka (2017): An
Expeditious Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in Aqueous Medium Using Thiamine
Hydrochloride (VB1) as a Mild, Efficient and Reusable Organocatalyst, Synthetic Communications,
DOI: 10.1080/00397911.2017.1337149
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1337149
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Date: 08 June 2017, At: 10:31

An Expeditious Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in Aqueous Medium
Using Thiamine Hydrochloride (VB1) as a Mild, Efficient and Reusable
Organocatalyst
Jutika Devi1, Subarna Jyoti Kalita1, Dibakar Chandra Deka1
1Department of Chemistry, University of Gauhati, Guwahati , Assam, India
Corresponding to author: Dibakar Chandra Deka E-mail: dcdeka@rediffmail.com
Abstract
A simple and straightforward synthesis of 2,3-dihydroquinazolin-4(1H)-ones is
developed by reacting anthranilamide with various aldehydes or ketones under mild
reaction conditions, using thiamine hydrochloride (VB1) as a cost-effective, readily
available and green catalyst in water. Simple purification process, high yields within
short reaction time, wide substrate scope, operational simplicity and reusability of the
catalyst up to three cycles enrich the applicability of the protocol.
GRAPHICAL ABSTRACT
Keywords: 2,3-Dihydroquinazolin-4(1H)-ones; Thiamine hydrochloride (VB1); Water;
Organocatalysis; Green chemistry
INTRODUCTION
1

In recent years, effort to design mild, selective and efficient catalytic systems with low
environmental impact has been one of the priorities for synthetic organic chemists. In this
context, organocatalysis has emerged as a center of renewed interest, bridging the gap
between metal and enzyme catalysis; thereby providing an alternative for metal mediated
organic synthesis.[1] In addition, organocatalysts offer many advantages because they are
moisture and air stable, easy to handle and store, relatively nontoxic, readily separable
from the crude reaction mixture and required only in substoichiometric amount.[1,2]
Further, to avoid the adverse implication arising from the use of organic solvents,
development of efficient synthetic methodology in water has been a great challenge for
synthetic chemists. Water is not only safe, abundant and nonflammable but also it
influences the course of the reaction with its unique physiochemical properties like
polarity, hydrogen bonding, hydrophobic effect and trans-phase interactions.[3] Owing to
these advantages, efforts to design aqueous media organocatalyzed reaction protocols[4]
for organic synthesis continue to be an active area of research.
Quinazolinones are an important class of heterocyclic compounds with a
wide range of biological and pharmacological activities as anticancer,[5]
antiinflammation,[6] antibacterial,[7] antiviral,[8] antimalarial,[9] anticonvulsant,[10]
antidepressant[11] and analgesic.[12] In addition, they also act as estrogen
receptors,[13] and CNS depressant[14]
-glucosidase,[15] rho
kinase,[16] and nonpeptidometic plasmepsin.[17] These scaffolds are often found as
the core units in various natural products and drug molecules;[18] whilst a number
2

of them have found applications in organic electroluminescence devices,[19] and as
metal ion sensors[20] which have further increased their synthetic value.
Due to their importance, a number of reports appear in the literature
describing the synthesis of these heterocycles from anthranilamide and aldehydes
or ketones using Sc(OTf)3,[21] Y(OTf)3,[22] Cerium(IV) ammonium nitrate
(CAN),[23] ZrCl4,[24] Co-CNTs,[25] cerous methanesulfonate,[26] Cu-nanoparticle,[27]
graphene oxide nanosheet,[28] ropylphosphonic anhydride (T3P®),[29] boehmite-Si-
DSA,[30] p-sulfonic acid calix[4]arene,[31] wang-OSO3H,[32] cellulose-SO3H,[33] β-
cyclodextrin-SO3H,[34] 2-morpholinoethanesulfonic acid,[35] amberlyst-15,[36] 1-
isopropyl-1,2,4-triazolium triflate,[37] starch sulfate,[38] tetrabutylammonium
-
bromide,[39] I2 in [bmim+][BF4 ],[40] NH4Cl,[41] L-proline nitrate,[42]
-
cyclodextrin[43] and cyanuric chloride[44] as catalysts. Although these methods are
useful, some of them suffer from one or more drawbacks like longer reaction time,
high temperature, unsatisfactory yield, non reusability of the catalyst and limited
substrate scope. Further, the complex synthetic procedures for some of the
catalysts, harsh reaction conditions, the use of toxic organic solvents, application
of metals, salts, acids and ionic liquids as catalysts increase the waste generation
and cost of the synthesis, which thereby reduce its applicability. It may be noted
that recently, Chan et al. have reported a thiamine hydrochloride (VB1) catalyzed
synthesis of 2,3-dihydroquinazolin-4(1H)-ones by three component reaction of
isatoic anhydride, aldehydes and ammonium acetate in ethanol as the solvent
system (Scheme 1a).[45] Although, this reaction is very efficient in obtaining 2,3-
3

dihydroquinazolin-4(1H)-ones in high yields, but it is associated with limitations
like the use of organic solvent, deficiency in atom economy, longer reaction time
and substrate compatibility only to aromatic aldehydes. Therefore, development of
simple, efficient and cost-effective synthetic strategy for this important class of
compounds under environmentally benign reaction conditions continues to be an
active area of research. With these background, and in continuation to our efforts
on the development of environment-friendly protocols for organic synthesis,[46]
herein we wish to report a new organocatalytic approach for the selective and
straightforward synthesis of 2,3-dihydroquinazolin-4(1H)-ones by the reaction of
anthranilamide with aldehydes or ketones using thiamine hydrochloride (VB1) as a
reusable catalyst in water under mild reaction conditions (Scheme 1b).
In significance, the present protocol proves to be operationally simple and affords high
yield under mild reaction conditions. The use of thiamine hydrochloride (VB1) as the
catalyst and water as the solvent system provides cost-effectiveness and environmental
benignity. Structurally, vitamin B1 consists of a pyrimidine ring and a thiazole ring linked
by a methylene bridge and has found a wide range of applications in organic synthesis.
VB1 is a catalyst of choice due to the facts that it is easy to handle, inexpensive, non-toxic
and readily available.47 On the whole, high yields, shorter reaction time, simple work-up
procedure, wide substrate scope and operational simplicity make the applicability of the
protocol highly attractive for the synthesis of a huge library of 2,3-dihydroquinazolin-
4(1H)-ones.
4

RESULTS AND DISCUSSION:
Initially, a mixture of anthranilamide (1) and benzaldehyde (2a) in 5 mL water was
refluxed in the presence of 5 mol% VB1 for 1 h, and gratifyingly the desired product 2-
phenyl-2,3-dihydroquinazolin-4(1H)-one (3a) was obtained in 70% yield (Table 1, entry
1). Inspired by this result, the reaction was set for optimization and was found that 10
mol% VB1 in 5 mL water, under reflux condition are the optimum reaction conditions
which furnish 3a with maximum yield of 87% in 20 min, since there is no further
improvement of yield or decrease in reaction time when the catalyst load was increased
up to 15 mol% (Table 1, entries 2 and 3). Potential Lewis acids like FeCl3.6H2O and
NiSO4.6H2O were also tested, but failed to catalyze the reaction efficiently (Table 1,
entries 4 and 5). In order to find the solvent effect, when the reaction was performed in
EtOH, MeOH, and toluene, it was observed that the desired product was formed, but in
relatively lower yields (Table 1, entries 6-8). Also an attempt to obtain the desired
product at room temperature and under catalyst free condition failed (Table 1, entries 9
and 10).
Having arrived at the optimized reaction conditions, the scope of the
methodology was explored by reacting anthranilamide with various aldehydes, and
the results are recorded in Table 2. Various aromatic aldehydes participated well in
the reaction and the desired products were obtained in good to high yields. The
presence of electron donating or withdrawing group in ortho-, meta- and para-
positions of the benzene ring of various benzaldehydes has no significant impact
on the reaction, and the corresponding 2,3-dihydroquinazolin-4(1H)-ones (3a-3j)
5

were obtained successfully. Heteroaromatic aldehydes like 4-
pyridinecarboxaldehyde and 2-pyridinecarboxaldehyde also participated well in
the reaction and their corresponding products 3l and 3m were obtained in
satisfactory yields. Gratifyingly, polyaromatic aldehyde like 2-napthaldehyde also
reacted efficiently and its corresponding product 3k was obtained in 81% yield.
Aliphatic aldehyde like valeraldehyde also reacted smoothly to afford the product
3n in 74% yield. Ketones like cyclopentanone, cycloheptanone and acetone were
found to be equally compatible under the optimized reaction conditions, and when
used in place of aldehydes, these ketones smoothly furnished the corresponding
products 3o, 3p and 3q in 83, 80 and 85% yield respectively. However, aromatic
ketone like acetophenone failed to give the desired product. The scope of the
method was further extended towards the synthesis of bis-2,3-dihydroquinazolin-
4(1H)-one by reacting anthranilamide (1, 1 mmol) and terepthalaldehyde (2r, 0.5
mmol) under the same optimized reaction conditions, and the desired product 3r
was obtained in 87% yield within 20 min (Scheme 2).
All the synthesized compounds were characterized by 1H, 13C NMR, IR, mass spectral
and elemental analysis. The known compounds were further authenticated from literature
reports.
Next, to add further credibility to the protocol we did test the reusability of the catalyst
for the model reaction of anthranilamide and benzaldehyde under the optimized reaction
conditions. Since VB1 is soluble in water and the product is insoluble, at the end of the
6

reaction, the desired product was isolated by simple filtration and the filtrate containing
the catalyst was reused. It is observed that VB1 is reusable up to three cycles without any
significant difference in reaction time, product yield and catalytic activity (Table 3).
Mechanistically, the reaction is believed, based on literature reports,[47] to undergo
VB1 assisted initial condensation between anthranilamide (
ketone ( ) to generate the Schiff base intermediate which subsequently
undergoes VB1 promoted intramolecular nucleophilic addition, followed by proton
transfer to generate the final product (Scheme 3).
1) and an aldehyde or a
2
4
3
In summary, we have demonstrated a new and highly efficient procedure for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones from anthranilamide and various
aldehydes or ketones under environmentally benign reaction conditions using
thiamine hydrochloride (VB1) as the catalyst in water. The application of VB1 as
organocatalyst and water as reaction medium make the protocol cost-effective and
expand the scope of organocatalyzed aqueous media organic synthesis. On the
whole, provided by the efficiency and the reusability of the catalyst, wide substrate
scope, high yields, operational simplicity, simple and easy purification process
make the protocol highly attractive for the synthesis of a huge library of
biologically active 2,3-dihydroquinazolin-4(1H)-ones.
EXPERIMENTAL
7

IR spectra were recorded on a SHIMADZU infrared spectrometer as KBr pellets
and the absorption expressed in cm–1. 1H and 13C NMR spectra were recorded in
CDCl3 or DMSO-d6 on 300 or 400 MHz Bruker or JEOL NMR spectrometer at ≈
25 °C with tetramethylsilane (TMS) as the internal standard, and resonances ( )
are given in ppm. Data are reported as follows: chemical shift ( ), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet), coupling constants (Hz) and
integration. LCMS were obtained on Waters ZQ 4000 equipped with ESI source.
Melting points were determined using Veego VMP-D and not corrected. Elemental
analysis was done on Perkin Elmer Series II Analyzer 2400. Thin Layer
Chromatography (TLC) was performed using Merck pre-coated silica gel or silica
gel G and the components were visualized under a UV or an iodine chamber.
General Procedure For The Synthesis Of 2,3-Dihydroquinazolin-4(1H)-Ones (3a-3q)
A mixture of anthranilamide (1, 1 mmol) and aldehyde or ketone (2, 1 mmol) in 5
mL water was refluxed for appropriate time in the presence of 10 mol% thiamine
hydrochloride (VB1) as the catalyst (Table 2). On completion of the reaction, as
indicated by TLC, the crude reaction mixture was cooled to room temperature and
the precipitate was filtered out and washed with water (10 mL x 3) to get the pure
product. Whenever necessary, the products were further purified by
recrystallization from ethanol.
Procedure For The Synthesis Of Bis-2,3-Dihydroquinazolin-4(1H)-One (3r):
8

A mixture of anthranilamide (1, 1 mmol) and terepthalaldehyde (2r, 0.5 mmol)
was refluxed in presence of 10 mol% thiamine hydrochloride (VB1) for 20 min
(Scheme 2). On completion of the reaction as indicated by TLC, the crude reaction
mixture was cooled to room temperature and the precipitate was filtered out and
washed with water (10 mL x 3) to get the pure product in 87% yield.
ACKNOWLEDGMENTS
The authors thank UGC, Govt of India for the financial assistance. The authors
also thank SAIF-NEHU, GU, IIT Guwahati and IIT Ropar for the sample analyses.
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14

Table 1. Optimization of the reactiona
Catalyst (mol%)
VB1 (5)
Temp (oC)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
RT
Time (min)
Yield (%)c
Entry
Solventb
H2O
1
60
20
20
20
20
20
20
20
60
60
70
87
87
55
40
81
83
25
20
35
2
VB1 (10)
H2O
3
VB1 (15)
H2O
4
FeCl3.6H2O (10)
NiSO4.6H2O (10)
VB1 (10)
H2O
5
H2O
6
EtOH
MeOH
Toluene
H2O
7
VB1 (10)
8
VB1 (10)
9
VB1 (10)
10
-----------
H2O
Reflux
aReaction scale:
1
and 2a (1 mmol each). b5 mL. c Isolated Yield
15

Table 2. Scope of the synthesisa
3a (87%)b; 20 min
3b (80%)b; 25 min
3e (84%)b; 30 min
3c (83%)b; 20 min
3f (85%)b; 20 min
3i (85%)b; 20 min
3d (80%)b; 25 min
3h (82%)b; 15 min
3g (86%)b; 20 min
3j (80%)b; 30 min
3m (80%)b; 30 min
3k (81%)b; 20 min
3n (74%)b; 45 min
3l (76%)b; 35 min
3o (83%)b; 15 min
16

3p (80%)b; 15 min
3q (85%)b; 25 min
a Reaction scale: 1 (1 mmol), 2 (1 mmol) and H2O (5 mL). b Isolated yield.
17

Table 3. Reusability of the catalyst
Time (min)
Yield (%)a
Entry
Reaction cycle
Fresh
1
2
3
4
5
20
20
20
20
25
87
85
82
80
77
First recycle
Second recycle
Third recycle
Fourth recycle
a Isolated yields
18

Scheme 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
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Scheme 2. Synthesis of bis-2,3-dihydroquinazolin-4(1H)-one.
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Scheme 3. Plausible reaction mechanism.
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