One-pot, multicomponent sequential synthesis of benzothiazoloquinazolinones

Article abstract of DOI:10.1080/00397910903243807

Benzothiazolo[2,3-b]quinazolin-1-ones have been synthesized by a multicomponent reaction of substituted 2-aminobenzothiazoles with cyclic β-diketone and aromatic aldehydes in the presence of absolute ethanol. The structures of the synthesized benzothiazoloquinazolinones have been characterized by elemental analysis and spectral studies. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903243807

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One-Pot, Multicomponent
Sequential Synthesis of
Benzothiazoloquinazolinones
Bhupesh K. Sharma a , Praveen Kumar Sharma a & M. Kumar a
a Department of Chemistry, University of Rajasthan, Jaipur, India
Version of record first published: 26 Jul 2010
To cite this article: Bhupesh K. Sharma, Praveen Kumar Sharma & M. Kumar (2010): One-Pot,
Multicomponent Sequential Synthesis of Benzothiazoloquinazolinones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:16, 2347-2352
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Synthetic Communications1, 40: 2347–2352, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903243807
ONE-POT, MULTICOMPONENT SEQUENTIAL
SYNTHESIS OF BENZOTHIAZOLOQUINAZOLINONES
Bhupesh K. Sharma, Praveen Kumar Sharma, and M. Kumar
Department of Chemistry, University of Rajasthan, Jaipur, India
Benzothiazolo[2,3-b]quinazolin-1-ones have been synthesized by
a multicomponent
reaction of substituted 2-aminobenzothiazoles with cyclic b-diketone and aromatic
aldehydes in the presence of absolute ethanol. The structures of the synthesized benzothia-
zoloquinazolinones have been characterized by elemental analysis and spectral studies.
Keywords: 2-Aminobenzothiazoles; benzothiazoloquinazolinones; CDK and GSK-3 inhibitors; quinazo-
lines; thiazoloquinazolines
INTRODUCTION
The synthesis of fused heterocycles has attracted considerable interest in
heterocyclic chemistry because the fusion of biodynamic heterosystems has proved
to be a very attractive and useful for the design of new molecular frameworks for
potential drugs of varying pharmacological activities. There has been increasing
interest in the chemistry of quinazolines[1,2] because the quinazoline heterocyclic sys-
tem is a building block in many natural and synthetic products that exhibit a wide
variety of biological and pharmacological activities.[3] Quinazolines have been
reported to exhibit anticonvulsant, antibacterial, antidiabetic, and anticancer activi-
ties. Benzothiazole has also been an interesting heterocyclic system in drug research
on account of the significant biological activities of its fused derivatives.[4] Thiazolo-
quinazolines, incorporating both biodynamic heterosystems thiazole and quinazo-
line, have shown significant activity against cancer.[5] Thiazoloquinazolines have
also been identified as cyclin dependent kinase (CDK) and glycogen synthase
kinase-3 (GSK-3) inhibitors.[6]
RESULTS AND DISCUSSION
The methods reported in the literature[7] for the synthesis of thiazoloquinazo-
lines, irrespective of positions of attachment of both the heterocyclic systems, involve
multiple steps in which the formation of thiazole ring before the quinazoline ring
induced low subsequent reactivity. Thiazoloquinazolines prepared by reaction of
Received May 27, 2009.
Address correspondence to M. Kumar, University of Rajasthan, Department of Chemistry, JLN,
Marg, Bapu Nagar, Jaipur 302055, India. E-mail: mahendrakpathak@yahoo.com
2347

2348
B. K. SHARMA, P. K. SHARMA, AND M. KUMAR
2-aminobenzylamine with aromatic amine and then with 2-mercaptopropionic acid
also involve multistep reactions. In continuation of our research program on the syn-
thesis of nitrogen- and sulfur-containing novel heterocycles[8] of pharmaceutical
interest and in view of the simplicity of multicomponent reactions and their potential
to introduce considerable structural diversity,[9] we have synthesized benzothiazo-
lo[2,3-b]quinazolinones, incorporating two biodynamic heterocyclic systems, by a
simple and efficient multicomponent reaction. The reaction involves a three-
component cyclocondensation of 2-aminobenzothiazole with cyclic b-diketone and
an aromatic aldehyde in the presence of absolute ethanol (Scheme 1).
The reaction is believed to proceed with Knoevenagal condensation between
cyclic b-diketone and an aromatic aldehyde in the initial step to form an a,b-unsatu-
rated ketone, which undergoes Michael-type addition with the nucleophilic endocyc-
lic nitrogen of 2-aminobenzothiazole under reflux. The adduct formed is then
cyclized intramolecularly with the loss of water molecule to provide benzothiazo-
lo[2,3-b]quinazolinones. These reactions have taken place in one flask in a domino
manner, and the enone system generated in situ immediately undergoes Michael-type
addition with 2-aminobenzothiazole and subsequent cyclization. The structures of
the synthesized compounds were confirmed by their elemental analysis and spectral
studies. The regioselectivity of the process has also been confirmed by theoretical stu-
dies that show the endocyclic nitrogen is more nucleophilic than the amino group.
The possibility of formation of the isomeric product involving nucleophilic attack
of exocyclic amino group has been completely discarded.
Infrared (IR) spectra of all the synthesized compounds exhibit an intense
carbonyl absorption band in the region 1680–1660 cmÀ1. The absorption band in
the region 1620–1604 cmÀ1 in the IR spectra of all the compounds indicated the
=
presence of C N bonds. Two absorption bands corresponding to asymmetric and
symmetric stretching vibrations of the –NH2 group, which were present in the IR
spectra of 2-aminobenzothiazoles, are absent in the IR spectra of the synthesized
1
compounds. H NMR spectra of the synthesized compounds showed a multiplet
in the region d 7.16–7.54 ppm due to aromatic protons. The singlet in the region d
6.47–6.58 ppm was assigned to the aliphatic proton (12-H).The singlet observed in
the region d 3.73–3.77 ppm was attributed to the methoxy protons, whereas the
methyl protons resonate as a singlet in the region d 2.34–2.36 ppm in the 1H
NMR spectra of thiazoloquinazolinones containing –OCH3 and –CH3 groups at
position 10. The multiplets observed in the regions d 2.00–2.05 ppm and d
Scheme 1.

ONE-POT SYNTHESIS OF BENZOTHIAZOLOQUINAZOLINONES
2349
2.22–2.28 ppm were assigned to the two methylene protons at C-4, whereas other
multiplets observed in the regions d 2.52–2.57 ppm and d 2.59–2.66 ppm were attrib-
uted to two methylene protons at C-2. The methylene protons present at C-3 also
appeared as multiplets in the region d 1.44–1.73 ppm. In the 13C NMR spectra of
the synthesized benzothiazoloquinazolinones, the d values of most of the carbon
atoms could be determined and assigned to the corresponding carbon atoms.
In conclusion, we have presented a simple and convenient multicomponent
one-pot synthesis of biologically and pharmaceutically interesting benzothiazo-
lo[2,3-b]quinazolinones. The present method enables the sequential combination of
three reactive components in one pot and efficiently incorporates structural diversity
simply by varying the substituent or by slight structural modification in the compo-
nents involved in the reaction. The structural diversity in molecules makes for effec-
tive pharmacophoric interactions with the receptor sites in the biological system.
EXPERIMENTAL
The purities of all the synthesized compounds have been checked by thin-layer
chromatography (TLC) using various nonaqueous solvents. The IR spectra were
recorded on a Nicolet-Magna Fourier transform (FT)–IR spectrophotometer, model
550, in KBr discs. 1H NMR spectra have been recorded on a Jeol FX-90 QFT NMR
spectrometer at 90 MHz in dimethylsulfoxide (DMSO-d6)=CDCl3 containing tetra-
methylsilane (TMS) as an internal standard. Data are presented in Table 1.
General Procedure for the Preparation of
Benzothiazolo[2,3-b]quinazolinones
A stirred solution of 2-aminobenzothiazole (0.01 mol), cyclic b-diketone
(0.01 mol), and aromatic aldehydes (0.01 mol) in absolute ethanol (20 ml) was
refluxed for 30–40 min in a round-bottomed flask fitted with reflux condenser
(Scheme 1). The precipitate formed was isolated by filtration. The solid that sepa-
rated out was washed well with ethanol, dried, and finally crystallized from ethanol.
Selected Data for Benzothiazolo[2,3-b]quinazolinones
À1
À1
Compound 4b. Mp 181–183 ꢀC; FT-IR (KBr): 1665 cm (C O), 1620 cm
=
À1
1
=
(C N), 720 cm (C-Cl); H NMR (300 MHz, CDCl3): d 7.18–7.50 (m, 8H), 6.52
(s, 1H), 2.54–2.62 (m, 2H), 2.25–2.34 (m, 2H), 2.03–2.15 (m, 2H), 1.78 (s, 3H); 13C
NMR d (75 MHz, CDCl3): 26.4, 30.2, 40.1, 49.7, 54.1, 116.6, 120.6, 121.4, 122.8,
126.5, 127.0, 127.4, 128.2, 130.2, 140.4, 144.9, 145.2, 163.8, 194.6. Anal. calcd.
C21H17ClN2OS: C, 62.22; H, 4.50; N, 7.35. Found: C, 65.85; H, 4.99; N, 7.33.
À1
À1
Compound 4h. Mp 194–196 ꢀC; FT-IR (KBr): 1680 cm (C O), 1616 cm
=
À1
1
=
(C N), 712 cm (C-Cl); H NMR (300 MHz, CDCl3): d 7.18–7.74 (m, 8H), 6.53
(s, 1H), 3.77 (s, 3H), 2.54–2.63 (m, 2H), 2.25–2.32 (m, 2H), 2.01–2.12 (m, 2H),
1.78 (s, 3H); 13C NMR d (75 MHz, CDCl3): 29.3, 39.6, 48.6, 53.5, 166.4, 117.6,
118.3, 122.3, 127.4, 128.6, 134.5, 149.2, 154.6, 162.2, 194.3. Anal. calcd.
C21H17ClN2O2S: C, 63.22; H, 4.79; N, 7.01. Found: C, 63.55; H, 4.32; N, 7.06.

2350
B. K. SHARMA, P. K. SHARMA, AND M. KUMAR
Table 1. Reaction of 2-aminobenzothiazoles with cyclic b-diketone and aromatic aldehydes
2-Aminobenothiazol
Cyclie b-diketone
Aldehyde
Product
Mp (ꢀC)
Yield (%)
4a
181
60
2
2
2
4b
4c
4d
194
154
167
64
72
56
2
2
4e
4e
183
189
67
74
2
2
4f
180
194
65
64
4g
ACKNOWLEDGMENTS
The authors are thankful to the head of the Department of Chemistry, Univer-
sity of Rajasthan, Jaipur, India, for providing the necessary laboratory facilities as

ONE-POT SYNTHESIS OF BENZOTHIAZOLOQUINAZOLINONES
2351
well as instrumentation facilities. We express our thanks to the University Grants
Commission, New Delhi, for providing a meritorious student fellowship to P. K. S.
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