A versatile one-pot multicomponent synthesis of novel quinazolinon-2-yl- tetrasubstituted thiophenes

Article abstract of DOI:10.1016/j.tetlet.2010.08.046

Here, we report a versatile multicomponent synthesis of novel quinazolinon-2-yl-tetrasubstituted thiophenes by a one-pot reaction using different alkyl-3-aminobutenoates, isothiocyanates and 2-halomethyl quinazolinones in good to excellent yields. The reaction probably proceeds by an intramolecular 5-exo-trig cyclisation.

Full text of DOI:10.1016/j.tetlet.2010.08.046

Tetrahedron Letters 51 (2010) 5686–5689
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A versatile one-pot multicomponent synthesis of novel
quinazolinon-2-yl-tetrasubstituted thiophenes
⇑
Hitesh B. Jalani, Jitendra C. Kaila, Arshi B. Baraiya, Amit N. Pandya, 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:
Here, we report a versatile multicomponent synthesis of novel quinazolinon-2-yl-tetrasubstituted
thiophenes by a one-pot reaction using different alkyl-3-aminobutenoates, isothiocyanates and 2-halom-
ethyl quinazolinones in good to excellent yields. The reaction probably proceeds by an intramolecular
5-exo-trig cyclisation.
Received 30 June 2010
Revised 14 August 2010
Accepted 17 August 2010
Available online 20 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Quinazolinon-2-yl-tetrasubstituted
thiophenes
Alkyl-3-aminobutenoates
Isothiocyanates
5-exo-Trig
Multicomponent reactions (MCRs), by virtue of their conver-
gence, productivity, facile execution and generally high yields of
products, have attracted much attention from the vantage point of
combinatorial chemistry.1,2 Especially one-pot multicomponent
processes have recently gained a considerable and steadily increas-
ing academic, economic and ecological interest because they ad-
dress very fundamental principles of synthetic efficiency and
reaction design.3 Additionally, the prospect of extending one-pot
reactions into combinatorial and solid-phase synthesis4,5 promises
manifold opportunities for developing novel lead structures of phar-
maceuticals, catalysts and even novel molecule-based materials.
4(3H)-Quinazolinone and related quinazoline scaffolds are a
class of fused heterocycles that are of considerable interest because
they possess diverse range of biological properties. The quinazoli-
none moiety is a building block for more than 150 naturally
occurring alkaloids6 such as glycosminine7, echinozolinone,8
deoxyvasicinone,9–11 rutaecarpine12 and drugs like methaqua-
lone.13 The natural quinazolinones and their synthetic analogues
possess a variety of biological activities, including antimalarial,14
anticonvulsant,15,16 antibacterial,17 antidiabetic18 and anticancer
activities.19 Examples include the anticancer compound trimetrex-
ate, the sedative methaqualone, the alpha-adrenergic receptor
antagonist such as doxazosin and the antihypertensive agent
ketanserin. The quinazoline moiety is known to have inhibitory
effects on receptor tyrosine kinases, which are promising targets
recent days in cancer chemotherapy, which includes approved
drugs such as erlotinib, lapatinib and gefitinib (Fig. 1). In addition
to this, quinazolines of the type CU-16020 have also been found to
be inhibitors of NF-kB proteins. NF-kB proteins are a class of ‘rapid-
acting’ transcription factors that regulate the expression of more
than 400 target genes and play a pivotal role in several important
physiological processes including immune and inflammatory re-
sponses.21 Thus, due to the diverse range of the pharmacological
activities of quinazolinone derivatives, there has been an enor-
mous interest in the synthesis of quinazolinone using versatile
methods. There are numerous methods available for the synthesis
of quinazolines.22
⇑
Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail address: perd@perdcentre.com (K.K. Vasu).
Figure 1. Some biologically important molecules incorporating quinazoline
scaffold.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.046

H. B. Jalani et al. / Tetrahedron Letters 51 (2010) 5686–5689
5687
Scheme 1.
Thiophene is an important structural motif in medicinal chemis-
try and numerous methods for its synthesis have been reported.23–26
Fascinated by working on fragment tethering approach,27 we
observed that the substitution of different heterocyclic moieties
such as thiophene at position 2 of quinazolinone nucleus28 modu-
lates anti-inflammatory effect and anti-cancer activity by inhibiting
the transcription factors29,30 (Fig. 1). The relevance of compounds
composed from two or more heterocyclic rings for drug discovery,
regardless of the target, can be best documented by the frequency
with which bis-heterocyclic compounds were identified as the most
potent ones.31
In the context of our ongoing interest for the development of
new routes for small heterocyclic compounds bearing especially
amino group at the position 2 of the heterocycles, we have been
working on the reaction of various alkyl-3-aminobutenoates with
different isothiocyanates to produce the alkyl-3-aminobutenoate:
isothiocyanate adducts, which can be further explored for the syn-
thesis of heterocyclic compounds. Enaminones are readily avail-
able chemical intermediates and their chemistry has received
considerable attention in the recent years.32 As far as the chemical
reactivity of alkyl-3-aminobutenoates (here after: enamino esters)
is concerned, they can react with both the electrophiles and the
neucleophiles as mentioned in the literature.33–36 We were inter-
ested in the use of enamino esters as neucleophiles, in particular
their reaction with isothiocyanates.
have checked the reaction of electron-releasing (–CH3 and
–OCH3) groups as well as electron-withdrawing (–Cl) groups pres-
ent in the phenyl ring of isothiocyanates. Electron-releasing groups
present in phenyl ring of isothiocyanates gave better yields as com-
pared to their counterpart electron-withdrawing groups. Even the
reaction of 2-bromomethyl quinazolinone 3a with enamino ester
and isothiocyanates was very fast and completed within 3–4 h.
Furthermore we checked the generality of this reaction using
2-chloromethyl 3-substituted quinazolinones (3b–d) with the ena-
mino esters and isothiocyanates to produce thiophene compounds
(entries 4n–r) but the reactions were slower in comparison with
2-bromomethyl quinazolinones. In order to hasten the reaction
rate for the synthesis of 4n–r, a pinch of KI (Finkelstein reaction)
was added in the reactions of 2-chloromethyl 3-substituted qui-
nazolinones (Table 1). Other examples of this reaction involve
the use of 3,5-dichloro isothiocyanate and benzyl isothiocyanate
with enamino ester and quinazolinones to give (entry 4l and m).
In conclusion, we have reported a novel one-pot multicomponent
transformation involving three components such as enamino esters,
isothiocyanates and 2-halomethyl quinazolinones to yield function-
ally diverse quinazolinon-2-yl-tetrasubstituted thiophenes through
the C–C bond formation via an intramolecular 5-exo trig cyclisation
in good to excellent yields. The advantage of this method is its facile
The existing methods for the synthesis of quinazolinone-thio-
phene heterocycles connected through C–C bond involve the N-
acylation of 2-amino benzoic acids or 2-amino benzamides with
substituted or unsubstituted thiophene-2-carboxylic acid chloride,
followed by ring closure with or without the aid of various amines
to furnish the 2-thienyl quinazolinones.37 Synthesis of such build-
ing blocks involves number of steps. We have recently reported a
multistep process to prepare substituted thiophenes attached to
quinazolinone rings, and their use as potential anti-inflammatory
and anticancer agents.38 In order to simplify the process and to ob-
tain new derivatives, we have developed a one-pot, multicompo-
nent process which proceeds in good to high yields, and which is
reported herein.
We report here, a multicomponent reaction leading to quinazoli-
non-2-yl-tetrasubstituted thiophenes 4, by reacting different ena-
mino esters 1, isothiocyanates 2 and 2-halomethyl quinazolinones
3 in one pot to furnish 4 in good to excellent yields42 (Scheme 1).
A plausible reaction mechanism (Scheme 2) involves the reac-
tion of isothiocyanate 2 and enamino ester 1 to give intermediate
5. The resulting sulfide is a strong neucleophile and reacts with
2-halomethyl quinazolinone to afford the intermediate 6. In the
next step, an acidic proton of the methylene group is (formally) ab-
stracted by a halide ion, resulting in carbanion formation. This
carbanion then attacks the electrophilic imine carbon, producing
an intramolecular 5-exo-trig cyclisation followed by protonation
at the amine and undergoes NH3 and HBr eliminations, respec-
tively. Final step is the aromatisation of the ring by H-shift in order
to form a stable thiophene compound.
During the course of our study, it was observed that the reaction
of enamino ester of tertiary butyl acetoacetate gave better yields as
compared to enamino esters of methyl or ethyl acetoacetate. We
Scheme 2. A plausible reaction mechanism for quinazolinon-2-yl-tetrasubstituted
thiophene formation.

5688
H. B. Jalani et al. / Tetrahedron Letters 51 (2010) 5686–5689
Table 1
Synthesis of quinazolinon-2-yl-tetrasubstituted thiophenes (4a–r)
O
N
R3
O
N
N
R3 THF:ACN
R2
NH
R1
NH2
1
O
N
S
R2-N=C=S
2
+
R1
45-50ºC
+
X
O
DMF
4
3
O
O
Entry
R1
R2
R3
Product
Yielda (%)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
80
82
76
65
60
62
58
90
93
81
76
62
79
65
59
56
61
64
4-OCH3–C6H4
4-CH3–C6H4
4-Cl–C6H4
C6H5
4-OCH3–C6H4
4-CH3–C6H4
C6H5
4-OCH3–C6H4
4-CH3–C6H4
4-Cl–C6H4
3-Cl, 5-Cl–C6H3
CH2–C6H4
4-Cl–C6H4
4-OCH3–C6H4
C6H5
9
10
11
12
13
14
15
16
17
18
H
4-Cl–C6H4
4-Cl–C6H4
2-CH3–C6H4
2-OCH3–C6H4
2-OCH3–C6H4
C6H5
4-OCH3–C6H4
a
Isolated yield without chromatography, X = Br for entries 1–13 and Cl for entries 14–18.
16. Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.; Pagnozzi, M. J.; Kelly, K.;
Seymoyr, P. A.; Guanowsky, V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro,
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conditions and the product can be isolated very easily with excellent
purity and that too without the use of column chromatography. The
simplicity of the present process makes it an interesting alternative
to other approaches. Furthermore the presence of an amino group
ortho to the ester function in thiophenes makes them biologically
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Acknowledgements
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We thank Professor Harish Padh and Professor C.J. Shisoo, Direc-
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Supplementary data
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Supplementary data (general experimental procedures and
spectral data for new compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
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H. B. Jalani et al. / Tetrahedron Letters 51 (2010) 5686–5689
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42. General experimental procedure for the preparation of quinazolinon-2-yl-
tetrasubstituted thiophenes: A stirred solution of isothiocyanate 1 (1 mmol)
and enamino ester 2 (1 mmol) in a mixture of solvent tetrahydrofuran and
acetonitrile (1:1) was heated to 45–50 °C and maintained for 5–6 h. To this
mixture, a solution of 2-halomethyl quinazolinones 3 in DMF was added and
allowed to stir for another 3–4 h at room temperature. In case of
mixture was subjected to evaporation to remove low boiling solvents followed
by addition to the cold water to produce the precipitates. These precipitates
were filtered and dissolved in organic solvents such as ethyl acetate,
dichloromethane in which they are soluble, followed by drying over sodium
sulfate. The organic layer was then concentrated to give the crude compounds
which were further treated with diethyl ether and/or hexane to produce the
pure solid compounds (4a–r). The structures of compounds were assigned with
the help of NMR and mass spectra.
2-chloromethyl 3-substituted quinazolinone,
a pinch of potassium iodide
was added. Completion of the reaction was monitored by TLC. The reaction