An efficient, greener, and solvent-free one-pot multicomponent synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones

Article abstract of DOI:10.1016/j.tetlet.2012.05.104

Herein, we report an efficient, greener, and solvent-free novel method for the synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H) ones in a one-pot sequence using methyl anthranilate or 2-aminothiophene-3- carboxylate with N,N′-dimethyl formamide dimethyl acetal and various anilines. The driving force for this reaction is the removal of N,N′-dimethylamine by various anilines resulting in 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones.

Full text of DOI:10.1016/j.tetlet.2012.05.104

Tetrahedron Letters 53 (2012) 4062–4064
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient, greener, and solvent-free one-pot multicomponent synthesis of
3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones q
⇑
Hitesh B. Jalani, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, V. Sudarsanam, Kamala K. Vasu
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054,
Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report an efficient, greener, and solvent-free novel method for the synthesis of 3-substituted
quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones in a one-pot sequence using methyl anthranilate
or 2-aminothiophene-3-carboxylate with N,N0-dimethyl formamide dimethyl acetal and various anilines.
The driving force for this reaction is the removal of N,N0-dimethylamine by various anilines resulting in
3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones.
Received 6 February 2012
Revised 21 May 2012
Accepted 23 May 2012
Available online 29 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
3-Substituted-quinazolin-4(3H)ones
3-Substituted-thienopyrimidin-4(3H)ones
Greener approach
Formamidine
One pot reaction
Lots of efforts have been directed toward the design and appli-
cations of multicomponent reactions1 because MCRs are powerful
tools for the construction of organic molecules allowing the forma-
tion of several bonds in just a single reaction. In addition to this,
carrying out such multicomponent reactions with non hazardous
and environment friendly reagents could provide an interesting
platform to the scientific community over the conventional ap-
proaches. To minimize the use of hazardous reagents, emphasis
should be given to the development of greener approaches.
Quinazolin-4(3H)one is an important class of heterocycles
which possess diverse range of biological properties such as anti-
malarial,2 anticonvulsant,3 antibacterial,4 antidiabetic,5 and anti-
cancer activities.6 Diverse range of the pharmacological activities
of quinazolin-4(3H)one derivatives have tempted considerable
interest for the synthesis of quinazolin-4(3H)one using versatile
and greener methods. The most common method for the synthesis
of 3-substituted quinazolin-4(3H)one involves the reaction of
anthranilic acid with DMF and POCl3, reported by Perumal et al.7
Other methods for the synthesis of 3-substituted quinazolin-
4(3H)ones are from anthranilic acid derivatives.8–17 Recently, qui-
nazolin-4(3H)ones were prepared using silica sulfuric acid,18
PCl3,19 Zn/HCOONH4 under microwave irradiation,20 LiNO3,21 and
HATU.22 However, some of these methods are associated with
drawbacks such as multistep reactions, costly reagents, harsh reac-
tion conditions, complex and tedious experimental procedures,
and low yields.
Considering the above facts, there is still need to develop effi-
cient, greener, and economical methods for the synthesis of quinaz-
olin-4(3H)ones. In addition to this, a majority of the condensed
pyrimidin-4(3H)one heterocyclic compounds have been reported
from 2-aminobenzoic acid.8 Earlier reports on the synthesis of
3-substituted quinazolin-4(3H)ones incorporate anthranilic acid
as starting material, which has electron rich carboxylate resonance
structure thus requires various lewis acid catalysts in order to be-
come electron deficient for the cyclization. In case of methyl anthra-
nilate, the carbonyl group being electrophilic in nature, allows the
nucleophilic attack facile for the cyclization without use of any cat-
alysts. To the best of our knowledge, the formation of 3-substituted
quinazolin-4(3H)ones from methyl anthranilate has not been re-
ported so far.
In continuation to our work on the synthesis of biologically
important heterocycles such as quinazolin-4(3H)ones,23 we were
interested to investigate the formamidine intermediate resulting
from the reaction of methyl anthranilate and N,N0-dimethyl form-
amide dimethyl acetal (DMF–DMA) can further converted to qui-
nazolin-4(3H)ones with the help of various amines. The synthesis
of formamidine using either amines or thioureas with DMF–DMA
is well documented in the literatures.24 This formamidine structure
has tempted us to utilize it in the synthesis of quinazolin-4(3H)ones
by heating it with various amines to elicit the 3-substituted quinaz-
olin-4(3H)ones. Herein, we report an efficient, greener, sequential
one-pot method for the synthesis of 3-susbstitued quinazolin-
4(3H)ones from methyl anthranilate, DMF–DMA, and various
q
Communication Ref. No.: PERD-010512.
⇑
Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail address: kamkva@gmail.com (K.K. Vasu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.104

H. B. Jalani et al. / Tetrahedron Letters 53 (2012) 4062–4064
4063
O
work-up of this reaction gave the off-white crystalline solid. The for-
mation of this product was confirmed by Mass, 1H NMR, and 13C
NMR spectrometry. The synthesis of 3-(p-tolyl)quinazolin-
4(3H)one via HATU mediated coupling of 4-hydroxyquinazoline
and 4-aminotoluene22 provided only 41% yield, while the present
method provides 79% yield for the same compound suggesting the
advantage of the present method over the earlier methods for the
synthesis of 3-substituted quinazolin-4(3H)ones in many aspects
such as percentage overall yield, use of simple and non-hazardous
starting materials or reactants, avoiding the use of sophisticated
catalysts, solvent-free reaction conditions, all suitable for large scale
synthesis.
O
N
O
N
NH2
H
O
O
O
-HNMe2
-MeOH
N
O
+
N
R
+
H
N
NH2
-2MeOH
H
R
3
1
2
4
Scheme 1. One pot synthesis of 3-substituted quinazolinones.
amines. This method neither requires any reagent for the cyclization
nor the solvents (Scheme 1).
We started our effort by carrying out the reaction of methyl
anthranilate 1 and DMF–DMA 2 at warm condition, which resulted
in the removal of methanol to give the formamidine intermediate.
This formamidine intermediate was then reacted with
various amines 3 at elevated temperature to obtain 3-substituted
quinazolin-4(3H)one 4 which was showing different Rf value as
compared to the starting material formamidine on TLC. Further
Thus, in a representative experiment, the sequential reaction of
methyl anthranilate 1 and DMF–DMA 2 at 85–90 °C temperature
allows the removal of solvent methanol to give the formamidine
intermediate. This formamidine intermediate was then reacted
Table 1
3-Substituted quinazolin-4(3H)ones and 5,6,7,8-tetrahydrobenzthieno[2,3-d]pyrimidin-4(3H)ones
Entry Compounds 4 and 6
Yielda
(%)
Reaction time NMR spectral analysis (400 MHz, DMSO-d6, chemical shift in d ppm)
(h)
Melting range
(°C)
O
1H = 8.31 (s, 1H), 8.19 (d, 1H), 7.86 (m, 1H), 7.74 (d, 1H), 7.58 (m, 1H), 7.41 (d, 2H),
7.36 (d, 2H), 2.40 (s, 3H, –CH3)
144–146
N
1
2
3
4
79
82
72
67
12
(144–145)25
N
O
H
4a
O
1H = 8.30 (s, 1H), 8.18 (d, 1H), 7.79 (m, 1H), 7.68 (d, 1H), 7.52 (m, 1H), 7.38 (d, 2H),
7.31 (d, 2H), 3.84 (s, 3H, –OCH3)
191–193
N
N
11
(193–194)25
N
O
H
H
4b
4c
139–141
15
17
1H = 8.39 (d, 1H), 8.20 (s, 1H), 7.85 (m, 2H), 7.56 (m, 4H), 7.28 (m, 2H)
1H = 8.32 (d, 1H), 8.24 (s, 1H), 7.80 (m, 2H), 7.55 (m, 3H), 7.36 (d, 2H)
(141–142)25
N
O
Cl
F
179–181
N
N
(180–181)26
N
O
H
H
4d
4e
1H = 8.31 (s, 1H), 8.21 (d, 1H), 7.89 (m, 1H), 7.75 (d, 1H), 7.61 (m, 1H), 7.43 (d, 2H),
7.28 (d, 2H)
204–206
5
6
64
61
18
17
(203–205)25
N
O
O
1H = 8.38 (d, 1H), 8.23 (s, 1H), 8.15 (d, 2H), 7.83 (m, 2H), 7.56 (m, 3H), 2.62 (s, 3H, –
CH3)
196–198
163–165
225–228
N
N
N
O
H
H
4f
1H = 8.16 (s, 1H), 8.19 (d, 1H), 7.86 (m, 1H), 7.74 (d, 1H), 7.58 (m, 1H), 7.22 (s, 1H),
7.18 (m, 2H), 2.03 (s, 6H, –CH3)
7
8
76
80
16
12
N
O
N
4g
O
1H = 8.12 (s, 1H), 8.24(d, 1H), 7.89 (m, 1H), 7.78 (d, 1H), 7.60 (m, 1H), 6.92 (s, 1H),
6.95 (m, 2H), 3.78 (s, 6H, –OCH3)
N
O
H
4h
O
1H = 8.29 (s, 1H), 7.40 (d, 2H), 7.33 (d, 2H), 2.37 (s, 3H, –CH3), 2.70 (m, 2H), 2.63 (m, 141–143
2H), 1.75 (m, 4H)
N
9
10
11
12
64
66
63
56
22
20
23
24
(140–142)27
6a
S
N
O
H
O
1H = 8.20 (s, 1H), 7.38 (d, 2H), 7.32 (d, 2H), 3.87 (s, 3H, –OCH3), 2.65 (m, 2H), 2.59 (m, 134–136
N
N
2H), 1.56 (m, 4H)
(134–135)27
6b
S
S
N
O
H
H
186–188 (186–
189)27
1H = 8.33 (s, 1H), 7.42 (d, 2H), 7.37 (m, 3H), 2.66 (m, 2H), 2.64 (m, 2H), 1.61 (m, 4H)
6c
N
O
Cl
175–177
1H = 8.37 (s, 1H), 7.44 (d, 2H), 7.38 (d, 2H), 2.69 (m, 2H), 2.67 (m, 2H), 1.63 (m, 4H)
N
(176–178)27
6d
S
N
H
a
Yields refer to isolated products. Melting points of compounds are uncorrected.

4064
H. B. Jalani et al. / Tetrahedron Letters 53 (2012) 4062–4064
C.J. Shishoo Directors of B.V. Patel PERD centre, for their constant
encouragement and support.
O
NH2
-HNMe2
O
O
N
H
O
O
N
O
O
R
+
N
+
H
N
-EtOH
-2MeOH
S
S
S
N
H
NH2
R
3
2
References and notes
6
5
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V. A.; Greef, M. Synthesis 2003, 1471; (c) Hulme, C.; Gore, V. Curr. Med. Chem.
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Organometallic Chemistry; Muller, T. J. J., Ed.; Springer: Berlin, 2006; Vol. 19, p
149; (k)Multicomponent Reactions; Zhu, V., Bienaym, H., Eds.; Wiley-VCH:
Weinheim, 2005.
2. Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M. A.; Kim, H. S.; Wataya, Y.;
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Scheme 2. One pot synthesis of 3-substituted tetrahydrobenzo[b]thieno[2,3-
d]pyrimidin-4(3H)ones.
with p-toluidine 3a at the same temperature to obtain the desired
3-(p-tolyl)quinazolin-4(3H)one 4a. Further work up of this reac-
tion gave the off-white crystalline solid.28 The structure of this
compound was confirmed by 1H NMR, 13C NMR, (Table 1) and Mass
spectrums. In addition to this, the present protocol is also useful for
the construction of 3-substituted 5,6,7,8-tetrahydrobenzothie-
no[2,3-d]pyrimidin-4(3H)ones from 2-aminothiophene-3-carbox-
ylate, DMF–DMA, and various amines (Scheme 2).
During the course of study, it was observed that the reaction of
electron rich anilines furnished very good yield (4a, b, g, h), while
the electron deficient anilines resulted in comparatively lower
yields (4d–f) as shown in Table 1. It was also observed that anilines
substituted with electron releasing groups require less time to
form the formamidine intermediate (6–10 h) while electron with-
drawing groups present in amines require comparatively more
time to furnish the formamidine (12–16 h). Further, it is also
observed that the reaction of DMF–DMA with liquid reactants like
methyl anthranilate (homogeneous mixture) required less time
(10–18 h) for the formation of the quinazolin-4(3H)ones, while
the solid substrate like 2-aminothiophene-3-carboxylate (due to
heterogeneous reaction mixture) required more time (18–24 h)
for the thienopyrimidin-4(3H)ones with comparatively less yields.
According to the Sigma-Hammett equation, if the electron donat-
ing group is present at the para position of anilines, then the sigma
value is negative. In case of anilines with electron donating groups
(EDG) there will be an enhancement in the nucleophilic character
as compared to the electron withdrawing group (EWG) and there-
by the formamidine intermediate will probably be a rate limiting
step, therefore, EDGs comparatively result in yield higher than
the EWGs (Table 1). The difference between the yield from EDG
and EWG groups present in anilines for the quinazolin-4(3H)ones
synthesis is not significant.
In conclusion, we have demonstrated a novel, efficient, and
greener one-pot method for the synthesis of 3-substituted quinazo-
lin-4(3H)ones and thienopyrimidin-4(3H)ones from simple starting
materials like methyl anthranilate or 2-amino-3-carbethoxy thio-
phenes, N,N0-dimethylformamide dimethyl acetal, and various ani-
lines to afford products in good to excellent yields. The present
method is attractive due to its solvent-free condition, no use of
any costly lewis acid catalyst and environment friendly conditions
suggesting this protocol could be an alternative to other protocols.
The product can be isolated very easily without the use of
chromatography in most cases. Furthermore the synthesis of
pyrrolopyrmidin-4(3H)ones, pyrazolopyrmidin-4(3H)ones, and
furopyrimidin-4(3H)ones using this methodology is under
development.
5. Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Lingard, L.; Risen, L. M.; Vickers, T.
A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999,
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28. General experimental procedure for the preparation of 3-substituted-
quinazolinones/thienopyrimidinones: In
a
hot air dried flask, methyl
(1.0 mmol) and
anthranilate or 2-amino-3-carbethoxy thiophenes
1
5
dimethylformamide dimethyl acetal 2 (1.1 mmol) were mixed together and
heated to 85–90 °C for 6–18 h. Progress of the reaction was monitored by TLC
using ethyl acetate/hexane (2:8). When the TLC shows the consumption of
starting material, amine 3 (1.0 mmol) was added with stirring. The reaction
was then again maintained at the same conditions for another 10–18 h (in case
of thiophene 12–24 h). After completion of the reaction, the reaction mixture
was then evaporated to remove the methanol and dimethyl amine from the
reaction mass. The reaction mixture was treated with hexane to remove the
volatiles and unreacted materials. Then it was poured into cold water, upon
stirring precipitates were observed and collected on a Buchner funnel. (If there
were no precipitates, particularly in case of thienopyrimidinones, the reaction
mixture was extracted in the suitable solvent and purified by column
chromatography.). These precipitates were then dissolved in either
dichloromethane or ethyl acetate and dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residues were treated
with hexane and/or ether to give the pure compounds (4a–h/6a–d).
Acknowledgments
We gratefully acknowledge the financial support for this work
from B.V. Patel PERD centre. Dr. Hitesh B. Jalani thanks the Indus-
trial Commissioner (IC) of Gujarat for the grant provided to carry
out research work. We thank Dr. Manish Nivsarkar and Professor