Synthesis of fused thiazolo[3,2-a]pyrimidinones: N-aryl-2-chloroacetamides as doubly electrophilic building blocks

Article abstract of DOI:10.1016/j.tetlet.2013.11.001

2-Chloro-N-phenylacetamide and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide are doubly electrophilic building blocks for the formation of ring annulated thiazolo[3,2-a]pyrimidinone products. This synthetic route involves formation of the title compound in acceptable product yields by the elimination of the by-product, aniline/2-aminobenzothiazole. Analytical and spectral studies, as well as single crystal X-ray data on the representative compound 6c confirmed the structure of all the reaction products.

Full text of DOI:10.1016/j.tetlet.2013.11.001

Tetrahedron Letters 55 (2014) 224–226
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of fused thiazolo[3,2-a]pyrimidinones: N-aryl-2-
chloroacetamides as doubly electrophilic building blocks
b
Janardhan Banothu a, Srinivas Basavoju a, Rajitha Bavantula a, , Peter A. Crooks
⇑
a Department of Chemistry, National Institute of Technology, Warangal 506 004, A.P., India
b Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Chloro-N-phenylacetamide and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide are doubly electrophilic
building blocks for the formation of ring annulated thiazolo[3,2-a]pyrimidinone products. This synthetic
route involves formation of the title compound in acceptable product yields by the elimination of the
by-product, aniline/2-aminobenzothiazole. Analytical and spectral studies, as well as single crystal
X-ray data on the representative compound 6c confirmed the structure of all the reaction products.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 August 2013
Revised 30 October 2013
Accepted 1 November 2013
Available online 13 November 2013
Keywords:
Thiazolo[3,2-a]pyrimidinones
2-Chloro-N-phenylacetamide
N-(Benzo[d]thiazol-2-yl)-2-
chloroacetamide
Single crystal X-ray analysis
Thiazolo[3,2-a]pyrimidinones have emerged as molecules with
potentially useful therapeutic properties that have gained consid-
erable attention from both synthetic and medicinal chemists due
to their versatile biological activities, which include antimicrobial,1
anticancer,2 antioxidant,3 antitumor,4 anticonvulsant,5 antiinflam-
matory,6 antinociceptive,7 analgesic, antiparkinsonian,8 antiviral,9
and antibiofilm properties.10 Such compounds have also been re-
ported as 5-HT2 receptor antagonists,11 and inhibitors of xanthine
oxidase,12 CDC25B phosphatase13 enzymes, and the Bcl-2 family of
proteins.14
Owing to these remarkably broad pharmacological properties, a
variety of synthetic methods have been reported for the prepara-
tion of thiazolo[3,2-a]pyrimidinone derivatives involving the cycli-
zation of 3,4-dihydropyrimidin-2(1H)-thiones with halogen-
derived doubly electrophilic building blocks such as chloroacetic
acid,6,9,10,15 bromoacetic acid,2,8 chloroacetyl chloride,13 methyl
chloroacetate,16 ethyl bromoacetate,4 and 2-haloacetamides.17
Most of these methods utilize bases such as sodium acetate, trieth-
ylamine, and potassium hydroxide. Recently, Abbas et al.18 have
reported a regioselective isocyanide-based three-component reac-
tion for the synthesis of thiazolo[3,2-a]pyrimidinone derivatives at
ambient temperature.
4-dihydropyrimidin-2(1H)-thiones to form fused thiazolo[3,2-a]
pyrimidinone derivatives.
The general synthetic pathway to the title compounds,
fused thiazolo[3,2-a]pyrimidinones (6a–f and 7a–d), is illustrated
in Scheme 1. The intermediate fused 3,4-dihydropyrimidin-
2(1H)-thiones (4a–f and 5a–d) were synthesized by the
three-component condensation of
a 6-substituted-1-tetralone
(1a,b), an aromatic aldehyde (2), and thiourea (3) utilizing
S
R
+
Ar CHO
+
H2N NH2
O
3
2
1a: R = H; 1b: R = OCH3
(i)
O
R'
Cl
Ar
Ar
N
Ar
N
N
H
H
N
O
R'
NH
N
N
(8,9)
(ii)
R' NH2
+
X
N
H
S
S
S
Solvent
Reflux
R
R
R
6(a-f): R = H
7(a-d): R = OCH3
10,11(a-f): R = H
12,13(a-d): R = OCH3
4(a-f): R = H
5(a-d): R = OCH3
N
S
8/10/12: R' = Ph; 9/11/13: R' =
In this Letter, we wish to report the utilization of 2-chloro-N-
phenylacetamide and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide
as the source of building blocks for the ring annulation of 3,
Scheme 1. Synthesis of fused thiazolo[3,2-a]pyrimidinone derivatives. Reaction
conditions: (i) P(4-VPH)HSO4 (0.015 g), solvent-free, 120 °C, 10–20 min (yield: 88–
94%); (ii) method A: 2-chloro-N-phenylacetamide (8), without or with Et3N/AcONa/
KOH (base), acetic acid, reflux, 4–6 h; method B: N-(benzo[d]thiazol-2-yl)-2-
chloroacetamide (9), without or with Et3N/AcONa/KOH (base), 1,4-dioxane, reflux,
4–6 h.
⇑
Corresponding author. Tel.: +91 0870 2459445; fax: +91 0870 2459547.
E-mail address: rajitabhargavi@yahoo.com (B. Rajitha).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.001

B. Janardhan et al. / Tetrahedron Letters 55 (2014) 224–226
225
poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4] as a cat-
alyst under solvent-free conditions at 120 °C.19 The desired prod-
ucts (6a–f and 7a–d) were obtained in moderate yields by
cyclization of 4a–f and 5a–d with 2-chloro-N-phenylacetamide
(8)/N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (9) and elimina-
tion of the aniline/2-aminobenzothiazole under conventional heat-
ing in acetic acid/1,4-dioxane. 2-Chloro-N-phenylacetamide (8)
and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (9) were pre-
pared according to literature procedures20 by treatment of aniline
and 2-aminobenzothiazole with chloroacetyl chloride doped with
baked potassium carbonate in acetone/benzene under reflux.
Ghorab et al.21 have reported the synthesis of 5-aryl-8,9-dihy-
dro-3-phenyl-5H-thiazolo[2,3-b]quinazolin-6(7H)-ones by the
treatment of 4-aryl-1,2,3,4,7,8-hexahydro-2-thioxoquinazolin-
5(6H)-ones with phenacyl bromide in refluxing ethanol. This
prompted us to explore a similar strategy on fused 3,4-dihydropyr-
imidin-2(1H)-thiones utilizing 2-chloro-N-phenylacetamide in-
stead of phenacyl bromide. Thus, we carried out a reaction
utilizing equimolar quantities of 3,4,5,6-tetrahydro-4-phen-
ylbenzo[h]quinazoline-2(1H)-thione (4a) and 2-chloro-N-phenyl-
acetamide (8) in 10 mL of ethanol. As per the literature, we
expected the product to be the fused thiazolo[3,2-a]pyrimidine
(10a); however, the product obtained was identified as the fused
thiazolo[3,2-a]pyrimidinone (6a) based on analytical and spectral
data. The product 6a was obtained in only low yield (58%) in eth-
anol even after 12 h at reflux. The same reaction was also carried
out with N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (9) in place
of 2-chloro-N-phenylacetamide (8), and the same product (6a)
was obtained in 53% yield. In an attempt to improve the yield of
6a, the above reactions were carried out in a variety of solvents
such as acetic acid, acetonitrile, 1,4-dioxane, and dimethylformam-
ide at reflux temperature. The reaction conducted with 2-chloro-N-
phenylacetamide (8) in acetic acid afforded a maximal yield of 6a
(69%), while the reaction with N-(benzo[d]thiazol-2-yl)-2-chloro-
acetamide (9) in 1,4-dioxane returned a yield of 66% of 6a.
whereas in the presence of KOH the reactivity of 4e, 5c, and 5d
(possessing OH group) has decreased due to the formation of phen-
oxide ion which might hinder the cyclization step through the qui-
nonoid form, and afforded the corresponding products 6e, 7c, and
7d in only 5–15% yield. The structures of all the synthesized com-
pounds were confirmed from analytical and spectral studies (IR, 1H
NMR, 13C NMR, and mass spectral analysis) (see Supporting file),
and the structure of compound 6c was also determined from
single crystal X-ray diffraction. No fused thiazolo[3,2-a]pyrimidines
(10–13) were detected as products in the above reactions.
A plausible mechanism for the formation of the fused thiazol-
o[3,2-a]pyrimidinones is illustrated in Scheme 2. Reaction of
3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-2-thiol with 2-
chloro-N-phenylacetamide/N-(benzo[d]thiazol-2-yl)-2-chloroacet-
amide affords the intermediate thioether [A], which, on
intramolecular cyclization followed by the elimination of aniline/
2-aminobenzothiazole affords the title compounds.
Single crystal X-ray diffraction analysis of compound 6c was
carried out on crystals generated by slow evaporation in acetic
acid. X-ray diffraction data were collected on a CCD detector-based
diffractometer-SMART APEX from Bruker-Nonius AXS using Mo-K
a
radiation (k = 0.71073 Å) at 293 (2) K. The crystal structure was
solved by direct method using SHELXS-97 program, and refinements
of F2 were performed using SHELXL-97 program. A summary of the
crystallographic data, structure refinement details, supramolecular
C–HÁ Á ÁO dimer synthon, and packing diagram in the crystal struc-
ture are given in the supporting file. The ORTEP representation of
the molecular structure of 6c is shown in Figure 1.
We have developed a new synthetic route for the cycloconden-
sation of fused 3,4-dihydropyrimidin-2(1H)-thiones with 2-chloro-
N-phenylacetamide/N-(benzo[d]thiazol-2-yl)-2-chloroacetamide
to form fused thiazolo[3,2-a]pyrimidinone products. Here in this
H
O
O
Ar
N
Ar
Ar
N
Ar
H
N
H
N
R'
Cl
R
O
By adopting the above optimized reaction conditions, we have
synthesized a series of fused thiazolo[3,2-a]pyrimidinone deriva-
tives22 (6a–f and 7a–d) utilizing a variety of substituted 3,4,5,6-
tetrahydro-4-arylbenzo[h]quinazoline-2(1H)-thiones (4a–f and
5a–d). Several synthetic methodologies have been reported utiliz-
ing triethylamine/sodium acetate/potassium hydroxide as
base.4,10,16 Hence, we also carried out all the above reactions in
the presence of triethylamine, sodium acetate, and potassium
hydroxide,23 and the results are summarized in Table 1. On com-
paring these results (Table 1), we deduce that AcONa and Et3N
have not shown much affect on product yield and reaction time,
N
H
N
NH
NH
SH
R'
R'
NH
_
S
N
HCl
S
N
H
S
R
R
R
[A]
_
R' NH2
Ar
N
O
N
N
S
R = H / OCH3; R' = Ph /
S
R
Scheme 2. Plausible mechanism for the formation of fused thiazolo[3,2-a]
pyrimidinones.
Table 1
Synthesis of fused thiazolo[3,2-a]pyrimidinone derivatives
Producta
Ar
R
Time (h)
Method A
Method B
Et3N
Base-free
Yieldb (%)
Et3N
AcONa
KOH
Base-free
AcONa
KOH
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
C6H5
4-ClC6H4
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
5
4
5
4
6
6
6
4
5
4
69
70
72
64
67
65
65
70
73
68
68
72
70
61
63
65
64
70
71
68
67
66
68
60
68
65
63
71
69
69
62
67
69
63
10
60
62
67
15
15
5
4
4
4
6
5
5
5
4
4
66
68
69
65
62
62
63
67
71
67
68
69
66
66
60
63
63
66
73
66
62
65
65
63
60
60
65
68
72
64
62
63
66
66
5
59
60
62
5
4-OCH3C6H4
3,4-(OCH3)2C6H3
4-OHC6H4
3-NO2C6H4
C6H5
4-FC6H4
4-OHC6H4
4-OH-3-OCH3C6H3
10
a
Reaction conditions: method A: substituted 3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-2(1H)-thione (1 mmol), 2-chloro-N-phenylacetamide (1 mmol), without or
with Et3N/AcONa/KOH (0.5 mmol), acetic acid, reflux. Method B: substituted 3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-2(1H)-thione (1 mmol), N-(benzo[d]thiazol-2-yl)-
2-chloroacetamide (1 mmol), without or with Et3N/AcONa/KOH (0.5 mmol), 1,4-dioxane, reflux.
b
Isolated yields.

226
B. Janardhan et al. / Tetrahedron Letters 55 (2014) 224–226
7. Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W. Med. Chem. Res. 2010, 19, 1245–
1258.
8. Abd El-Galil, E. A.; Maigali, S. S.; Abdulla, M. M. Monatsh. Chem. 2008, 139,
1409–1415.
9. Mohamed, S. F.; Flefel, E. M.; Amra, A. E.; Abd El-Shafy, D. N. Eur. J. Med. Chem.
2010, 45, 1494–1501.
10. Pan, B.; Huang, R.; Zheng, L.; Chen, C.; Han, S.; Qu, D.; Zhu, M.; Wei, P. Eur. J.
Med. Chem. 2011, 46, 819–824.
11. (a) Ruiu, S.; Marchese, G.; Saba, P. L.; Gessa, G. L.; Pani, L. Mol. Psychiatr. 2000, 5,
673–677; (b) Fadi, M. A. Sci. Pharm. 2008, 76, 415–438.
12. Chandrahas, N. K.; Ragini, G. B.; Bhaskar, S. D.; Shankaraiah, G. K.; Namdev, T. K.
J. Enzyme Inhib. Med. Chem. 2010, 25, 615–621.
13. Kolb, S.; Mondesert, O.; Goddard, M.-L.; Jullien, D.; Villoutreix, B. O.;
Ducommun, B.; Garbay, C.; Braud, E. Chem. Med. Chem. 2009, 4, 633–648.
14. (a) Feng, Y.; Ding, X.; Chen, T.; Chen, L.; Liu, F.; Jia, X.; Luo, X.; Shen, X.; Chen, K.;
Jiang, H.; Wang, H.; Liu, H.; Liu, D. J. Med. Chem. 2010, 53, 3465–3479; (b) Zhou,
B.; Li, X.; Li, Y.; Xu, Y.; Zhang, Z.; Zhou, M.; Zhang, X.; Liu, Z.; Zhou, J.; Cao, C.;
Yu, B.; Wang, R. Chem. Med. Chem. 2011, 6, 904–921; (c) Xu, Y.; Zhou, M.; Li, Y.;
Li, C.; Zhang, Z.; Yu, B.; Wang, R. Chem. Med. Chem. 2013, 8, 1345–1352.
15. (a) Rashad, A. E.; Sayed, H. H.; Shamroukh, A. H. Phosphorus, Sulfur Silicon Relat.
Elem. 2005, 180, 2767–2777; (b) El-Baih, F. E. M.; Al-Rasheed, H. H.; Al-Hazimi,
H. M. J. Saudi Chem. Soc. 2005, 9, 575–596.
16. Kulakov, I. V.; Nurkenov, O. A.; Turdybekov, D. M.; Issabaeva, G. M.;
Mahmutova, A. S.; Turdybekov, K. M. Chem. Heterocycl. Compd. 2009, 45,
856–859.
17. Kulakov, I. V. Chem. Heterocycl. Compd. 2009, 45, 1019–1021.
18. Abbas, A. E.; Mahdieh, Z.; Ali, R. F.; Azizollah, H. Tetrahedron Lett. 2012, 53,
1351–1353.
19. Janardhan, B.; Rajitha, B.; Peter, A. C. J. Saudi Chem. Soc. 2012. http://dx.doi.org/
10.1016/j.jscs.2012.10.007.
Figure 1. ORTEP representation of compound 6c. Thermal ellipsoids are drawn at
50% probability level.
20. Rahul, V. P.; Premlata, K.; Dhanji, P. R.; Kishor, H. C. Med. Chem. Res. 2013, 22,
195–210.
21. Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Il Farmaco 2000, 55,
249–255.
synthetic procedure, 2-chloro-N-phenylacetamide and N-
(benzo[d]thiazol-2-yl)-2-chloroacetamide are both functioning as
1,2-dielectrophiles in a ring annulation reaction to afford thiazol-
o[3,2-a]pyrimidinones.
22. General experimental procedure (under base-free conditions): Method A:
A
mixture
of
an
appropriately
substituted
(1 mmol)
3,4,5,6-tetrahydro-4-
and 2-chloro-N-
arylbenzo[h]quinazoline-2(1H)-thione
phenylacetamide (1 mmol) was mixed with 10 mL of acetic acid and the
mixture stirred at reflux temperature for 4–6 h. After completion of the
reaction (monitored by TLC), the reaction mixture was kept aside overnight.
During this time, the crude thiazolo[3,2-a]pyrimidinone product separated out
as a solid, and was filtered and quenched three times with 10 mL of cold acetic
acid to remove the by-product aniline. All the compounds were purified by
recrystallization from acetic acid. Method B: A mixture of an appropriately
Acknowledgments
We thank the Director, National Institute of Technology, Warangal
for providing facilities for carrying out these studies under an RSM
project. One of the authors (J.B.) thanks the Ministry of Human
Resource DevelopmentfortheAwardofa Senior Research Fellowship.
substituted
3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-2(1H)-thione
(1 mmol) and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (1 mmol) was
mixed with 10 mL of 1,4-dioxane and the mixture stirred at reflux
temperature for 4–6 h. The progress of the reaction was monitored by TLC,
and after completion of the reaction the solid that separated out was filtered
and identified as 2-aminobenzothiazole. The filtrate was poured into ice cold
water, and the solid that formed was filtered, dried, and recystallised from
acetic acid to afford the pure thiazolo[3,2-a]pyrimidinone product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.
001.
23. General experimental procedure (in the presence of base): Method A: To a mixture
of an appropriately substituted 3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-
2(1H)-thione (1 mmol) and 2-chloro-N-phenylacetamide (1 mmol) in 10 mL of
acetic acid, triethylamine/sodium acetate/potassium hydroxide (0.5 mmol)
was added and stirred at reflux temperature for 4–6 h. After completion of the
reaction (monitored by TLC), the reaction mixture was poured into ice cold
water, thus the solid separated out was filtered, washed repeatedly with water,
and purified by recrystallization from acetic acid. Method B: To a mixture of an
References and notes
1. (a) Abdel-Mohsen, S. A. J. Chin. Chem. Soc. 2003, 50, 1085–1092; (b) Robert, A.
C.; Richard, A. G.; Zdzislaw, F. C. J. Med. Chem. 1974, 17, 1025–1027.
2. Flefel, E. E.; Salama, M. A.; El-Shahat, M. Phosphorus, Sulfur Silicon Relat. Elem.
2007, 182, 1739–1756.
3. Maddila, S.; Damu, G. L. V.; Oseghe, E. O.; Abafe, O. A.; Venakata Rao, C.;
Lavanya, P. J. Korean Chem. Soc. 2012, 56, 334–340.
4. Abu-Hashem, A. A.; Youssef, M. M.; Hussein, H. A. R. J. Chin. Chem. Soc. 2011, 58,
41–48.
5. Abd El-Latif, N. A.; Abd El-Galil, E. A.; Ibrahiem, A. A. Monatsh. Chem. 2007, 138,
559–567.
6. Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Il Farmaco 1999, 54, 588–
593.
appropriately
substituted
3,4,5,6-tetrahydro-4-arylbenzo[h]quinazoline-
2(1H)-thione (1 mmol) and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide
(1 mmol) in 10 mL of 1,4-dioxane, triethylamine/sodium acetate/potassium
hydroxide (0.5 mmol) was added and stirred at reflux temperature for 4–6 h.
The progress of the reaction was monitored by TLC. After completion of the
reaction the solid that separated out was filtered and identified as 2-
aminobenzothiazole. The filtrate was poured into ice cold water, and the
solid that formed was filtered, dried, and recystallised from acetic acid to afford
the pure thiazolo[3,2-a]pyrimidinone product.