Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

Article abstract of DOI:10.1016/j.tetlet.2016.12.067

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil.

Full text of DOI:10.1016/j.tetlet.2016.12.067

Accepted Manuscript
Microwave AssistedSynthesisof 2,3-Dihydro-4H-benzo[4,5]thiazolo[3,2-a]fu-
ro[2,3-d]pyrimidin-4-ones and 6,7-Dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyr-
imidin-5-ones Using Mn(OAc)3
Aslı Ustalar, Mehmet Yilmaz
PII:
S0040-4039(16)31722-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.067
TETL 48479
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 November 2016
16 December 2016
22 December 2016
Please cite this article as: Ustalar, A., Yilmaz, M., Microwave AssistedSynthesisof 2,3-Dihydro-4H-
benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-Dihydro-5H-furo[2,3-d]thiazolo[3,2-
a]pyrimidin-5-ones Using Mn(OAc)3, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.12.067
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Microwave Assisted Synthesis of 2,3-Dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-
d]pyrimidin-4-ones and 6,7-Dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones
Using Mn(OAc)3
Aslı Ustalar, Mehmet Yilmaz*
Department of Chemistry, Faculty of Arts and Sciences, Kocaeli University, 41380 Umuttepe,
Kocaeli, Turkey
Abstract
2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-
a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the
cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-
aminothiazole, respectively.
A
new class of compounds, 2,3-dihydro-4H-
and 6,7-dihydro-5H-furo[2,3-
benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones
d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical
addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A
preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent
(92%) inhibitory potential, comparable with the standard drug Donapezil®.
Keywords: manganese(III) acetate; radical addition; cyclization; microwave; single crystal
X-ray analysis; AchE inhibition
E-mail: mehmet.yilmaz@kocaeli.edu.tr
Phone: +90-262-3032058, Fax: +90-262-3032003
Introduction
Heterocyclic ring systems such as thiazole, benzothiazole, benzothiazolopyrimidine,
thiazolopyrimidine and dihydrofuran form the skeletal structures of molecules displaying a
wide-range of biological activities. Thiazole and benzothiazole containing compounds have
been reported to show antitumor, antimicrobial, anthelmintic, anti-leishmanial, anticonvulsant
and anti-inflammatory effects.1 Additionally, aminophenazole is used as an antidote for
barbiturates and opiates,2 chlormethiazole shows sedative and hypnotic effects3 and
amthamine is a histamine agonist.4 Ritanserin5 and setoperone6 are thiazoloprymidine
containing drugs used in the treatment of psychological diseases. Additionally, many

thiazolopyrimidine derivatives also show acetylcholine esterase inhibition,7 antioxidant and
antitumor activity8 and anti-inflammatory, antimicrobial and antiviral9 effects.
Primidobenzothiazoles10 and dihydrofuropyrimidines11 show antibacterial, anti-fungal and
anti-allergic activities.
It is known that transition metal salts (Mn+3, Co+3, Cu+2, Ce+4) which are able to
transfer single electrons, form -carbon radicals with enolizable functional groups and the
addition of this radical to unsaturated systems can be used to generate new C-C bonds.12
Among these metal salts, manganese(III) acetate13 and cerium(IV) ammonium nitrate14 are
widely used. Our research group has reported the radical addition and cyclization of various
active methylene compounds to unsaturated systems using manganese(III) acetate and
cerium(IV) ammonium nitrate, resulting in the formation of functionalized dihydrofuran
containing compounds.13f-r, 14i-k Herein, we report the Mn(OAc)3 mediated radical addition of
2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-
a]pyrimidin-5-one 2b to conjugated alkenes 3a-c,e and diene 3d under microwave irradiation,
leading to 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-one 4a-d and 6,7-
dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-one 4e-i derivatives in high yields.
Result and Discussion
It was previously reported that the starting compounds, 2-hydroxy-4H-
benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one15 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-
5-one16 2b, could be synthesized using carbon suboxide in 83% and 90% yield, respectively.
Herein, we used a modified method for the synthesis of these compounds.17 For this purpose,
2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a (93%) and 7-hydroxy-5H-
thiazolo[3,2-a]pyrimidin-5-one 2b (95%) were synthesized from the reaction of 2-
aminobenzothiazole 1a and 2-aminothiazole 1b, respectively, with bis(2,4,6-
trichlorophenyl)malonate17 in toluene at 100 C for 15 minutes.
Scheme 1. Synthesis of 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-
hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b.

The
microwave
assisted
radical
addition
of
various
alkenes
to
benzothiazolopyrimidine 2a or thiazolopyrimidine 2b, mediated by Mn(OAc)3, gave
dihydrobenzothiazolofuropyrimidine 4a-d and dihydrofurothiazolopyrimidine 4e-i containing
compounds, respectively. The best results were obtained at 150 °C, 350 W with 60 sec
reaction time; all results are given in Table 1. While the reaction of 2-hydroxy-4H-
benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a with styrene 3a gave dihydrofuran 4a in 40%
yield, the reaction of 2a with 1,1-diphenylethylene 3b gave 4b in 90% yield. Similar results
were obtained from the reactions of 2a with 4,4'-(ethene-1,1-diyl)bis(methylbenzene) 3c and
(E)-1-phenyl-1,3-butadiene 3d, to form dihydrofurans 4c (65%) and 4d (80%), respectively,
in good yields. 7,7-Diphenyl-6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-one (4e)
was obtained in 95% yield from the reaction between 7-hydroxy-5H-thiazolo[3,2-
a]pyrimidin-5-one 2b and 3b. Additionally, the treatment of 2 with 3c formed dihydrofuran 4f
in excellent yield (93%). Compound 4g (75%) was obtained from the radical cyclization of 2b
with 3d. The reaction between 2b and phenylcyclohexene 3e gave dihydrofuran 4h and
acetyloxylated-dihydrofuran 4i in 43% and 22% yield, respectively. Compound 4i was
obtained as a single diastereomer and its structure determined by 1H-NMR, 13C-NMR, HSQC
and COSY spectra. The configurations of compounds 4h and 4i were determined by NOESY
spectra; in 4h and 4i a strong correlation was observed between the H-5b proton and the
ortho-protons of the phenyl group. Based on these results, the Ph and H-5b protons are on the
same plane for both compounds and the Ph and acetyloxy groups in compound 4i are on
different planes.
Table 1. Addition reactions of compounds 2a and 2b with alkenes (3a-c,e) and diene (3d).a
1,3-Dicarbonyl Alkene
Dihydrofuran
Yieldb (%)
Entry
4a, 40
1
2a
2a
3a
3b
4b, 90
2

4c, 65
2a
2a
3
3c
3d
3b
4d, 80
4e, 95
4
5
2b
2b
4f, 93
4g, 75
6
3c
2b
2b
7
8
3d
4h, 43
4i, 22
3e
a Reaction conditions: 2a or 2b (1 mmol), alkene or diene (1.2 mmol), Mn(OAc)3 (2.5 mmol),
acetic acid (10 mL), microwave irradiation 150 °C, 350 W, 60 s.
b Isolated yield based on the 1,3-dicarbonyl compound.
A proposed reaction mechanism is shown in Scheme 1. Initially, an α-carbon radical B
is formed from the reaction of Mn(OAc)3 with A. Intermediate C then forms from addition of
the α-carbon radical to 1,1-diphenylethylene. Oxidation of the intermediate product to
carbocation D with Mn(OAc)3 and intramolecular cyclization of D forms the angular
compound E. Alternatively, using the enolic form of D, intramolecular cyclization of F results
in the formation of compound G. Judging by the single crystal X-ray analysis of compounds
4b18 and 4e,19 the cyclization step was determined to have followed pathway II (Scheme 1).

Scheme 2. Proposed mechanism for the formation of compounds 4a-i.
Scheme 3. Molecular structure of compound 4b and 4e. Displacement ellipsoids are drawn at
the 50% probability level. H-atoms are shown as small spheres of arbitrary radii. Only one
molecule in the asymmetric unit cell is shown.
In the inhibition study on acetylcholine esterase using the Ellman method,20 compound
4e showed 92% inhibition which was comparable with the standard commercial drug
Donapezil®.
Conclusion
As a result of this work, a new class of compounds were obtained under microwave
irradiation by the Mn(OAc)3 promoted addition of 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-
a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b to various
alkenes
in
high
yields.
Our
studies
on
the
synthesis
of
new
dihydrobenzothiazolofuropyrimidine 4a-d and dihydrofurothiazolopyrimidine 4e-i
compounds and our investigation of their biological activities are an ongoing process.
Acknowledgements
This study was financially supported by the Scientific and Technical Research Council of
Turkey (TBAG-112T884) and Kocaeli University BAP (2016/070). A. Ustalar thanks to
TUBITAK for doctoral fellowship.

Supplementary data
Copies of NMR spectra for all compounds, single crystal X-ray data for compounds 4b and 4e
(CCDC numbers 997074 and 997072, respectively). Supplementary data and crystallographic
data associated with this article can be found in the online version, at http://dx.doi.org/
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Highlights
Compounds 2a and 2b were obtained in high yields under mild reaction conditions.
Radical addition of 2a and 2b to various alkenes using Mn(OAc)3 was achieved.
New classes of compounds (4a-i) were synthesized under microwave irradiation.

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Microwave Assisted Synthesis of 2,3-Dihydro-4H-benzo
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[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-
Dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones Using Mn(OAc)3
Aslı Ustalar, Mehmet Yilmaz*
Department of Chemistry, Faculty of Arts and Sciences, Kocaeli University, 41380 Umuttepe, Kocaeli-Turkey