Synthesis and Growth Stimulant Properties of 2-Acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one Derivatives

Article abstract of DOI:10.1155/2017/8180913

A convenient, accessible, and high yield method for preparing of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) by treatment of acetoacetic acid ethyl ester with thiourea in sodium methylate was developed. The alkylation of the latter with 3-chloro-pentane-2,4-dione and further regioselective cyclization of intermediate compound (2) in high yield afforded 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3). The halogenation and some transformations of synthesized thiazolo[3,2-a]pyrimidine (3) due to its ketone group were carried out to obtain the corresponding carboxamide, carbothioamide, sulfonohydrazide, and oxime and its alkylated derivatives (5). At preliminary biological studies the synthesized compounds have shown growth stimulant properties. The activity of four of them was higher than 70%, compared with heteroauxin.

Full text of DOI:10.1155/2017/8180913

Hindawi
Journal of Chemistry
Volume 2017, Article ID 8180913, 8 pages
https://doi.org/10.1155/2017/8180913
Research Article
Synthesis and Growth Stimulant Properties of
2-Acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
Derivatives
Vergush A. Pivazyan,1 Emma A. Ghazaryan,2 Roza S. Shainova,1,2 Rafael A. Tamazyan,3
Armen G. Ayvazyan,3 and Aleksandr P. Yengoyan1,2
1National Agrarian University of Armenia, 74 Teryan Str., 0009 Yerevan, Armenia
2Armenian-Russian (Slavonic) State University, 123 H. Emin Str., 0051 Yerevan, Armenia
3STC OPC Molecule Structure Research Center of NAS RA, 26 Azatutyan Av., 0014 Yerevan, Armenia
Correspondence should be addressed to Aleksandr P. Yengoyan; ayengoyan@mail.ru
Received 12 October 2016; Revised 5 December 2016; Accepted 12 December 2016; Published 18 January 2017
Academic Editor: Xinyong Liu
Copyright © 2017 Vergush A. Pivazyan et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
A convenient, accessible, and high yield method for preparing of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) by
treatment of acetoacetic acid ethyl ester with thiourea in sodium methylate was developed. e alkylation of the latter with 3-chloro-
pentane-2,4-dione and further regioselective cyclization of intermediate compound (2) in high yield afforded 2-acetyl-3,7-dimethyl-
5H-thiazolo[3,2-a]pyrimidin-5-one (3). e halogenation and some transformations of synthesized thiazolo[3,2-a]pyrimidine (3)
due to its ketone group were carried out to obtain the corresponding carboxamide, carbothioamide, sulfonohydrazide, and oxime
and its alkylated derivatives (5). At preliminary biological studies the synthesized compounds have shown growth stimulant
properties. e activity of four of them was higher than 70%, compared with heteroauxin.
1. Introduction
[29], antidepressant [30], and antiviral [31, 32]. Some deriva-
tives are offered as acetylcholinesterase inhibitors [3], an-
tipsychotic agents [33], calcium antagonists [34], phosphate
inhibitors [35, 36], and 5-HT2A receptor antagonists [37].
However, to our surprise, there are virtually no data in
the literature about pesticidal and plant growth regulatory
properties of thiazolo[3,2-a]pyrimidines. Only a few studies
of pesticidal [38, 39], herbicidal [40], and growth regulatory
activities [41] of these systems derivatives may be noted.
Prompted by the potential importance of this con-
densed biheterocyclic system the present investigation was
undertaken to synthesize a series of novel thiazolo[3,2-
a]pyrimidines derivatives to obtain the new chemical means
of plants protection and growth regulators [42].
iazole and pyrimidine are classes of heterocycles that are
of considerable interest because of the wide range of their
biological properties. Among them there are many pharma-
ceutically important molecules and chemical means of plants
protection. iazolopyrimidines, which consist of these two
active pharmacophore heterocycles, can also be of interest as
potential bioactive molecules and have acquired a growing
importance in the field of medicinal chemistry. Due to the
great potential of both of the moiety, different scientists
synthesized a large number of thiazolopyrimidines deriva-
tives in particular thiazolo[3,2-a]pyrimidines with different
substituents to evaluate their various pharmacological activi-
ties. e survey of literature reveals that these fused bihete-
rocyclic compounds show pharmacological properties like
anti-inflammatory [1–3], bactericidal [4–9], analgesic and
antiparkinsonian [10], antifungal [6, 7, 9, 11–14], antioxidant
[6, 9, 15], anticancer [16–20], antimicrobial [9, 21–26], hypo-
glycemic [27], psychopharmacological [28], antituberculosis
2. Results and Discussion
2.1. Chemistry. As precursors for the synthesis of thi-
azolo[3,2-a]pyrimidines the substituted pyrimidines and

2
Journal of Chemistry
O
OH
NH
S
OH
NH2
H2N
O
O
NH
N
CH3ONa
H3C
OC2H5
H3C
N
H
S
H3C
N
S
N
H
S
H3C
(1C)
(1A)
(1B)
Scheme 1: Synthesis of 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one.
(1)
aminothiazoles are used. In most of the papers the syn-
thesis of initial pyrimidine-2-thione derivatives is carried
out via Biginelli multicomponent condensation reaction of
substituted aldehydes with 1,3-dicarbonyl compounds and
thiourea [3, 6, 8, 9, 13, 20, 23]. In some cases, pyrimidines
were obtained in two steps [20]. In these syntheses the
yield of pyrimidine derivatives was 50–85%. eir further
condensation with substituted acyl chlorides, halocarboxylic
acids esters, or dicarbonyl compounds affords thiazolo[3,2-
a]pyrimidine biheterocyclic systems. In order to acceler-
ate the synthesis of targeted thiazolo[3,2-a]pyrimidines and
increase their yield, some authors used MW irradiation [9,
14, 43] or catalysts [44, 45].
OH
HO
CH3
CH3
N
H3C
N
S
O
(2A)
O
O
N
N
CH3
HO
NH
H3C
N
H
S
e cyclization of pyrimidine derivatives may yield sev-
eral isomers, due to substitution position in pyrimidine cycle
in the intermediate product. To achieve regioselectivity, the
cyclization reaction was carried out with bromomalononitrile
[9] or via S-propargyl derivatives [44, 45].
CH3
S
HO
O
H3C
O
(2C)
(2B)
CH3
CH3
To obtain thiazolo[3,2-a]pyrimidines some authors use 2-
aminothiazoles as precursors. In these cases targeted com-
pounds were obtained by cyclization of 2-aminothiazole
derivatives with bis(methylthio)methylene malononitrile
[15], benzylidene malononitrile [9], 2-acetylbutyrolactone
[37], and formamide and formic acid [41]. In [14, 43] 2-ami-
nothiazole was used in Biginelli reaction instead of thiourea.
A series of thiazolo[3,2-a]pyrimidinones were synthesized
in a two-step procedure, using Eaton’s reagent to effect the
cyclization of 2-aminothiazoles [46].
In order to develop a convenient, accessible, and high
yield method for preparing of 6-methyl-2-thioxo-2,3-dihy-
dropyrimidin-4(1H)-one, in present investigation acetoacetic
acid ethyl ester was treated with thiourea in sodium methy-
late (Scheme 1). Obtained compound can exist in different
tautomeric forms (1A–1C). In 13C NMR spectra the signal of
double C=S bond at 175.83 ppm and in 1H NMR spectra one
broaden average absorption at 11.98 ppm are observed. ese
data indicate that 6-methyl-2-thioxo-2,3-dihydropyrimidin-
4(1H)-one has structure (1B).
To obtain targeted thiazolo[3,2-a]pyrimidine, compound
1 interacted with 3-chloro-pentane-2,4-dione (Scheme 2). At
this process the substitution may occur at sulfur or one of
cyclic nitrogen atoms, due to position of hydrogen atoms in
pyrimidine moieties. In 13C NMR spectrum of compound
2 the signal of C=S carbon atom has disappeared and in
1H NMR spectrum besides the signal of enol hydrogen
atom (17.30 ppm, integral intensity equal to 0.9) also the
second absorption for cyclic OH or NH group is observed
(12.20 ppm). ese data indicated that the substitution
O
O
CH3
N
O
N
H3C
H3C
N
S
S
CH3
(3C)
N
H3C
(3B)
O
H3C
Scheme 2: Synthesis of 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-
a]pyrimidin-5-one.
occurred at sulfur atom and depending on tautomerism
of heterocyclic ring and pentadione moiety the obtained
compound may be described by one of the structures (2A,
2B) or (2C). e heating of the latter in toluene at 125–
130∘C in the presence of toluene-4-sulfonic acid afforded
compound (3). e intramolecular dehydration and cycliza-
tion can occur from tautomers (2B) or (2C) and as a
result 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-
one (3B) or 2-acetyl-3,5-dimethyl-thiazolo[3,2-a]pyrimidin-
7-one (3C) can be obtained.
Since the further transformations have been carried out
on the basis of this compound (3), its structure was strictly
proved by X-ray diffraction analysis, whose data unambigu-
ously agree with the structure (3B) (Figure 1).
To introduce some pharmacophore groups into mol-
ecule structure, some transformations due to the ketone

Journal of Chemistry
3
O
N
O
N
O
N
CH3
CH3
CH3
O
X
N OH
N
N
N
CH3
CH3
S
S
S
CH3
H3C
H3C
H3C
(4a–c)
(3)
(4d)
O
N
O
N
CH3
CH3
Hal
O
N
OR
N
N
CH3
CH3
S
(6a,b)
Scheme 3: Transformations of 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one.
S
H3C
H3C
(5a,b)
O14
(1)
C6
C5
C13
N7
C12
O3
C10
C11
C2
O
N
O
C4
C8
NH
S(CH2)2Cl
N
N9
S
H3C
H3C
N
H
S(CH2)2Cl
C1
Figure 1: e structure of 2-acetyl-3,7-dimethyl-5H-thiazolo[3,2-
a]pyrimidin-5-one (3).
O
N
O
N
group were carried out. By interaction of ketone (3) with
semicarbazide, thiosemicarbazide, and 4-methylbenzenes-
ulfonohydrazide the corresponding 2-(1-(3,7-dimethyl-
5-oxo-5H-thiazolo[3,2-a]pyrimidin-2-yl)ethylidene)hydra-
zine-1-carboxamide (4a), 2-(1-(3,7-dimethyl-5-oxo-5H-thi-
azolo[3,2-a]pyrimidin-2-yl)ethylidene)hydrazine-1-carboth-
ioamide (4b), and Nꢀ-(1-(3,7-dimethyl-5-oxo-5H-thiazolo[3,
2-a]pyrimidin-2-yl)ethylidene)-4-methylbenzene-sulfono-
hydrazide (4c) were obtained (Scheme 3).
In accordance with literature data some heterocyclic
substituted oximes and their ethers show fungicidal [47–49],
herbicidal [50, 51], insecticidal [52], and growth stimulant
[49] activities. erefore, by reaction of ketone (3) with
hydroxylamine hydrochloride, the corresponding 2-(1-(hy-
droxyimino)ethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimi-
din-5-one (4d) was synthesized. e latter with alkyl halides
formed 3,7-dimethyl-2-(1-(propoxyimino)ethyl)-5H-thia-
zolo[3,2-a]pyrimidin-5-one (5a) and 3,7-dimethyl-2-(1-((2-
phenoxyethoxy)imino)ethyl)-5H-thiazolo[3,2-a]pyrimidin-
5-one (5b).
N
N
S
H3C
H3C
S
(7)
Scheme 4: Synthesis of 7-methyl-2,3-dihydro-5H-thiazolo[3,2-
a]pyrimidin-5-one.
carried out. As a result 2-((2-chloroethyl)thio)-6-methyl-
pyrimidin-4(3H)-one or 2-((2-chloroethyl) thio)-6-methyl-
pyrimidin-4(1H)-one could be formed (Scheme 4).
In 13C NMR spectrum of the synthesized compound the
signal of carbon atom of C=O bond is retained, and C=S bond
has disappeared. In 1H NMR spectrum the values of chemical
shif of methylene groups’ signals are conformed to S-
substitution. At the same time, in accordance with elemental
analysis and mass spectrum data (M + 1 = 169), there are
no chlorine atoms in the molecule of resulting product.
erefore, even at room temperature, the intermediate S-
substituted derivative is subjected to heterocyclization, and 7-
methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (7)
or 5-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one
may be formed. e data of 1H and 13C NMR spectra of the
reaction product are similar to those of compound (3), which
conform to structure (7).
We also carried out an electrophilic substitution in the
pyrimidine ring to synthesize the halogenated derivatives (6a
and 6b) of ketone (3) (Scheme 3).
To synthesize the condensed system with a saturated
thiazole cycle the reaction of starting 6-methyl-2-thioxo-2,3-
dihydropyrimidin-4(1H)-one with 1,2-dichloroethane was

4
Journal of Chemistry
Table 1: Growth stimulant activity of synthesized compounds 3–6.
2.2. Biological Evaluation. At preliminary screening the her-
bicidal, fungicidal, and growth regulatory activities of novel
synthesized compounds were studied. All preparations did
not possess noticeable herbicidal or antifungal properties, but
they showed the pronounced growth stimulant activity.
For the growth regulatory properties evaluation the
action of aqueous emulsions (25 mg/L and 50 mg/L) of syn-
thesized compounds on the germination, growth, and sur-
vivability of seeds and seedlings of dicotyledonous bean
(Phaseolus vulgaris L.) was studied and compared with that
of heteroauxin (IAA).
Two series of bean seeds were incubated for 24 hours
in an appropriate medium in the dark at 25∘C. en the
seeds were transplanted into soil and watered daily. e
experimental data calculations were produced in 20–25 days.
e number of the plants roots of each series, their length and
weight in the moist and dry forms, and their average values
were calculated. e results were compared with similar
data of plants placed in IAA solutions, and the activities of
preparations in comparison with IAA (in %) were determined
(Table 1).
Number
Growth stimulant activity compared with IAA (%)
a
100
IAA
b
100
a
79
3
b
49
a
64
4a
4b
4c
4d
5a
5b
6a
6b
b
10
a
75
b
13
a
39
b
66
a
72
b
57
a
54
b
66
a
55
b
42
Practically all targeted substances (3–6) have shown
growth stimulant properties. e most active compounds
(more than 70% compared to heteroauxin) were (3), (4b),
(4d), and (6b).
a
43
b
48
a
66
b
74
a
50 mg/L.
25 mg/L.
3. Experimental
e 1H NMR and 13C NMR spectra were recorded on
Varian Mercury-300 MHz (Varian, USA) spectrometer, in
b
the mixture of solvents DMSO-ꢀ6 + CCl (1 : 3), using
was stirred at room temperature for 3 h; then at cooling
3-chloro-pentane-2,4-dione (10 mmol) was added. e
reaction mixture was allowed to stand for 24 h at 25∘C; then
DMFA was evaporated at low pressure and the residue was
processed with water and filtered off.
4
tetramethylsilane as internal standard and IR spectra on
Avatar 330FT-IR (ermo Nicolet, USA) spectrometer, using
attenuated total reflectance (ATP) method. Mass spectra
were recorded on LC-MS system (Agilent, USA). e X-ray
analysis was done at room temperature on automated Enraf-
Nonius CAD-4 diffractometer. e reaction progress and
purity of the obtained substances were checked by using TLC
method on UV-254 plates (“Silufol,” Czech Republic) with
acetone/hexane mixture (2 : 1) as eluent. All melting points
were determined in open capillaries and are uncorrected.
Yield (1.68 g, 70%); white crystal; m.p. 188–190∘b.
1HNMR: ꢁ = 2.18 (s, 3H, 6-CH ); 2.22 [s, 6H, (CH ) ]; 5.92
3
3 2
(s, 1H, CH-pyrim.); 12.20 (b.s., 1H, OH-pyrim.); 17.30 (s, 0.9H,
OH-enol). Anal. Calcd for C H N \ S: C, 49.99; H, 5.03; N,
10 12
2
3
11.66; S, 13.34; found: C, 49.81; H, 4.91; N, 11.22; S, 13.00.
3.3. Synthesis of 2-Acetyl-3,7-dimethyl-5H-thiazolo[3,2-a]pyr-
imidin-5-one (3). A solution of compound 2 (10 mmol)
and catalytic amounts of toluene-4-sulfonic acid in toluene
(10 mL) was heated at 125–130∘C for 4 h. Afer toluene
evaporation water (20 mL) was added and compound 3 was
filtered off from the mixture.
3.1. Synthesis of 6-Methyl-2-thioxo-2,3-dihydropyrimidin-
4(1H)-one (1). To methanol (10 mL) was added sodium
(30 mmol) and then thiourea (10 mmol) and acetoacetic
acid ethyl ester (10 mmol). e mixture was boiled for 7 h,
methanol was evaporated, and the precipitate was dissolved
in water, neutralized with acetic acid, and filtered off.
Yield (1.65 g, 75%); light yellow crystals; m.p. 126–128∘b.
Yield (1.26 g, 90%); light yellow crystals; m.p. 275–277∘b.
1
IR (KBr): ] = 1695 and 1705 (C=O). HNMR: ꢁ = 2.25 (s,
1HNMR: ꢁ = 2.09 (s, 3H, 6-CH ); 5.52 (s, 1H, CH-pyrim.);
3
3H, 7-CH ); 2.57 (s, 3H, COCH ); 3.08 (s, 3H, 3-CH ); 5.96
3
3
3
11.98 [b.s, 2H, (NH) ]. 13C NMR: ꢁ = 17.88; 103.38 151.91;
(s, 1H, CH-pyrim.). 13C NMR: ꢁ = 16.06; 22.85; 30.30; 105.22;
120.99; 141.69; 160.16; 160.94; 162.60; 189.40. Anal. Calcd for
C H N \ S: C, 54.04; H, 4.54; N, 12.60; S, 14.42; found: C,
2
160.32; 175.83. Anal. Calcd for C H N OS: C, 42.24; H, 4.25;
5
6
2
N, 19.70; S, 22.55; found: C, 42.24; H, 4.25; N, 19.70; S, 22.55.
10 10
2
2
53.90; H, 4.39; N, 12.29; S, 14.08.
3.2. Synthesis of 3-((4-Hydroxy-6-methylpyrimidin-2-
yl)thio)pentane-2,4-dione (2). e mixture of 6-methyl-2-
thioxo-2,3-dihydropyrimidin-4(1H)-one (1) (10 mmol) and
KOH (10 mmol) in dimethylformamide (DMFA) (15 mL)
X-Ray Diffraction Analysis. Crystal data: C H N O S, mon-
10 10
2
2
˚
˚
oclinic, space group ꢂ211/, ꢃ = 14.106(3) A, ꢄ = 4.0190(8) A,
3
∘
˚
˚
ꢅ = 18.062(4) A, ꢆ = 103.32(3) , ꢇ = 996.4(4) A , ꢈ = 4,

Journal of Chemistry
5
ꢉ = 293(2) K, ꢀꢊ = 1.482 g cm−3, ꢋ(MoK ) = 0.304 mm−1,
Yield (1.65 g, 71%); white crystals; m.p. 214–216∘C.
ꢁ
3010 data were collected up to ꢌ
= 30∘ (ꢍ
= 0.025,
1HNMR: ꢁ = 2.23 (s, 6H, C=NCH and 7-CH ); 2.86 (s, 3H, 3-
int
ꢍꢂ
=
0.0678). Final ꢍ-indices mfaoxr 1591 reflections with
3
3
CH ); 5.89 (s, 1H, CH-pyrim.); 11.66 (s, 1H, OH). 13C NMR:
3
ꢎ > 2ꢏꢐꢎꢑ and 139 refined parameters are ꢍ1 = 0.0562,
ꢒꢍ2 = 0.1080 (ꢍ1 = 0.1283, ꢒꢍ2 = 0.1328 for all 2902
data). Crystallographic data for compound (3) have been
deposited with the Cambridge Crystallographic Data Centre,
deposition number CCDC 991572.
ꢁ = 14.13; 16.17; 22.77; 104.93; 119.48; 132.27; 146.48; 159.93;
161.59; 161.67. Anal. Calcd for C H N \ S: C, 50.62; H, 4.67;
10 11
3
2
N, 17.71; S, 13.51; found: C, 50.49; H, 4.51; N, 17.39; S, 13.18.
3.6. General Synthesis of Compounds (5a,b). In DMFA
(20 mL) consecutively KOH (10 mmol) and compound 4d
(10 mmol) were diluted. e solution was stirred at 20∘C
for 3 h till salt formation. Afer cooling propyl bromide or
(2-bromoethoxy)benzene (11 mmol) was added. e mixture
was allowed to stand for 24 h and then heated at 70–80∘C for
2 h. DMFA was evaporated at low pressure; the residue was
processed with water and filtered off. Compounds (5a,b) were
purified by recrystallization from hexane.
3.4. Synthesis of 2-(1-(3,7-Dimethyl-5-oxo-5H-thiazolo[3,2-
a]pyrimidin-2-yl)ethylidene)hydrazine-1-carboxamide (4a).
e mixture of compound 3 (10 mmol) and semicarbazide
hydrochloride (10 mmol) in water (10 mL) was heated at
100∘C for 4 h.
Yield (2.6 g, 89%); yellow crystals; m.p. 310–312∘C.
1HNMR: ꢁ = 2.25 (s, 3H, 7-CH ); 2.41 (s, 3H, C=NCH ); 2.85
3
3
(s, 3H, 3-CH ); 5.92 (s, 1H, CH-pyrim.); 7.25 and 8.20 (b.s, 2H,
3
NH ); 10.64 (s, 1H, NH). Anal. Calcd for C H N \ S: C,
3.6.1. 3,7-Dimethyl-2-(1-(propoxyimino)ethyl)-5H-thiazolo[3,
2
11 13
5
2
47.30; H, 4.69; N, 25.07; S, 11.48; found: C, 47.20; H, 4.55; N,
24.79; S, 11.08.
2-a]pyrimidin-5-one (5a). Yield (2.36 g, 85%); white crystals;
m.p. 70–72∘C. 1HNMR: ꢁ = 0.98 (t, ꢓ = 7.4, 3H, CH -Pr);
3
1.72 (m, 2H, CH ), 2.24 (s, 6H, C=NCH and 7-CH ); 2.83
2
3
3
General Synthesis of Compounds (4b,c). To a suspension
of thiosemicarbazide or toluene-4-sulfohydrazide (10 mmol)
in water (10 mL), 36% HCl (12 mmol) and compound 3
(10 mmol) were added. e mixture was heated at 100∘C for
4 h, cooled, and filtered off. e precipitate was purified by
boiling in ethanol (50%).
(s, 3H, 3-CH ); 4.11 (t, ꢓ = 6.6, OCH ); 5.90 (s, 1H, CH-
3
2
pyrim.). 13C NMR: ꢁ = 9.85; 14.86; 16.18; 21.77; 22.76; 75.50;
104.97; 118.02; 133.26; 147.11; 159.82; 161.53; 161.77. Anal. Calcd
for C H N \ S: C, 55.89; H, 6.13; N, 15.04; S, 11.48; found:
13 17
3
2
C, 55.90; H, 6.01; N, 14.69; S, 11.11.
3.6.2. 3,7-Dimethyl-2-(1-((2-phenoxyethoxy)imino)ethyl)-5H-
thiazolo[3,2-a]pyrimidin-5-one (5b). Yield (2.4 g, 67%);
white crystals; m.p. 125–127∘C. IR (KBr): ] = 1679 (C=O).
1HNMR: ꢁ = 2.24 and 2.26 (s, 3H, 3H, C=NCH and 7-CH );
3.4.1. 2-(1-(3,7-Dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-
2-yl)ethylidene)hydrazine-1-carbothioamide
(4b). Yield
1
(2.45 g, 84%); yellow crystals; m.p. 248–250∘C. HNMR: ꢁ
3
3
= 2.24 (s, 3H, 7-CH ); 2.39 (s, 3H, C=NCH ); 2.88 (s, 3H,
2.83 (s, 3H, 3-CH ); 4.23 and 4.49 (t, t, 4H, OCH CH O);
3
3
3
2
2
5.91 (s, 1H, CH-pyrim.); 6.82–7.28 (m, 5H, C H ). 13C NMR:
3-CH ); 5.90 (s, 1H, CH-pyrim.); 7.19 and 8.27 (b.s, 2H,
3
6
5
NH ); 10.55 (s, 1H, NH). 13C NMR: ꢁ = 16.48; 17.43; 22.85;
ꢁ = 15.14; 16.23; 22.76; 65.43; 72.54; 105.03; 114.02; 120.18;
128.76; 133.50; 148.06; 158.01; 159.82; 1161.55; 161.83. Anal.
Calcd for C H N \ S: C, 60.49; H, 5.36; N, 11.76; S, 8.97;
2
105.06; 121.77; 133.73; 140.41; 159.96; 161.66; 161.86; 178.99.
Anal. Calcd for C H N \S : C, 44.73; H, 4.44; N, 23.71; S,
11 13
5
2
18 19
3
3
21.71; found: C, 44.55; H, 4.29; N, 23.40; S, 21.39.
found: C, 60.52; H, 5.22; N, 11.49; S, 8.56.
3.4.2. Nꢀ-(1-(3,7-Dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimi-
din-2-yl)ethylidene)-4-methylbenzenesulfonohydrazide (4c).
Yield (3.25 g, 90%); white crystals; m.p. 208–210∘C. 1HNMR:
ꢁ = 2.21 and 2.22 (s, 3H, 3H, CH -C H and 7-CH ); 2.44 (s,
3.7. General Synthesis of Compounds (6a,b). e mixture
of compound 4d (10 mmol), chlorosuccinimide, or bromo-
succinimide (12 mmol) in acetic acid (20 mL) was heated
at 100–110∘C for 3 h. Afer acid evaporation the residue
3
6
5
3
was processed with water, neutralized with NaHCO till
3H, C=NCH ); 2.75 (s, 3H, 3-CH ); 5.86 (s, 1H, CH-pyrim.);
3
3
3
7.32–7.80 (m, 4H, C H ); 10.74 (s, 1H, NH). 13C NMR: ꢁ =
pH 8 and filtered off. Compounds 6a,b were purified by
6
4
recrystallization from hexane-benzene mixture (1 : 1).
16.14; 17.17; 20.94; 22.79; 104.92; 121.34; 127.52; 128.82; 133.48;
135.88; 142.64; 145.08; 159.95; 161.42; 161.79. Anal. Calcd for
C H N \ S : C, 52.29; H, 4.65; N, 14.35; S, 16.42; found: C,
3.7.1. 2-Acetyl-6-chloro-3,7-dimethyl-5H-thiazolo[3,2-a]pyr-
17 18
4
3
2
imidin-5-one (6a). Yield (2.0 g, 80%); light brown crystals;
52.11; H, 4.53; N, 14.02; S, 16.11.
m.p. 140–142∘C. 1HNMR: ꢁ = 2.43 (s, 3H, 7-CH ); 2.58
3
(s, 3H, COCH ); 3.10 (s, 3H, 3-CH ). Anal. Calcd for
3
3
3.5. Synthesis of 2-(1-(Hydroxyimino)ethyl)-3,7-dimethyl-
5H-thiazolo[3,2-a]pyrimidin-5-one (4d). To a solution of
hydroxyl amine (11 mmol) in water (10 mL), at cooling a
solution of NaOH (11 mmol) in water (5 mL) was added
dropwise and then compound 3 (10 mmol) and ethanol
(10 mL). e mixture was allowed to stand for 24 h and then
heated at 50–60∘C for 2 h, cooled, processed with water, and
filtered off.
C H ClN \ S: C, 46.79; H, 3.53; N, 10.91; S, 12.49; found:
10
9
2
2
C, 46.58; H, 3.41; N, 10.57; S, 12.06.
3.7.2. 2-Acetyl-6-bromo-3,7-dimethyl-5H-thiazolo[3,2-a]pyr-
imidin-5-one (6b). Yield (2.52 g, 84%); light brown crystals;
m.p. 90–92∘C. 1HNMR: ꢁ = 2.48 (s, 3H, 7-CH ); 2.57
3
(s, 3H, COCH ); 3.09 (s, 3H, 3-CH ). Anal. Calcd for
3
3

6
Journal of Chemistry
C H BrN \ S: C, 39.88; H, 3.01; N, 9.30; S, 10.65; found: C,
[5] H. H. Sayed, A. H. Shamroukh, and A. E. Rashad, “Synthesis
and biological evaluation of some pyrimidine, pyrimido[2,1-
b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives,” Acta
Pharmaceutica, vol. 56, no. 2, pp. 231–244, 2006.
[6] S. Maddila, G. L. V. Damu, E. O. Oseghe, O. A. Abafe, C.
Venakata Rao, and P. Lavanya, “Synthesis and biological studies
of novel biphenyl-3,5-dihydro-2H-thiazolopyrimidines deriva-
tives,” Journal of the Korean Chemical Society, vol. 56, no. 3, pp.
334–340, 2012.
10
9
2
2
39.69; H, 2.89; N, 8.91; S, 10.21.
3.8. Synthesis of 7-Methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyr-
imidin-5-one (7). A suspension of compound 3 (10 mmol)
and KOH (20 mmol) in DMFA (10 mL) was stirred for 3 h
till salt formation; then at cooling (0∘C) 1,2-dichloroethane
(10 mmol) was added dropwise and allowed to stand for 24 h
at room temperature. e mixture was filtered off, DMFA was
evaporated at low pressure, and the residue was processed
[7] T. D. Oza, A. Parikh, and V. Gudaparthi, “Synthesis and
biological screening of some novel 3-amino-4-arylidene-5-pyr-
azolones and thiazolo[3,2-ꢔ]pyrimidines,” Inernational Journal
of Pharmaceutical Sciences, vol. 3, no. 4, pp. 2775–2785, 2012.
with CHCl and then with ether.
3
Yield (1.2 g, 70%); white crystals; m.p. 118–120∘C. IR
(KBr): ] = 1660 (C=O). 1HNMR: ꢁ = 2.15 (s, 3H, 7-CH );
[8] M. A. Salama and S. A. El-Essa, “Synthesis and reactions
of some new 2,3-dihydro-5H-5,7-diarylthiazolo-[3,2-a]pyrim-
idine-3-one derivatives and their antibacterial and fungicidal
activity,” Indian Journal of Chemistry Section, vol. 42, no. 1, pp.
173–179, 2003.
3
3.49 (t, ꢓ = 7.7, 2H, SCH ); 4.34 (t, ꢓ = 7.7, 2H, NCH );
2
2
5.83 (s, 1H, CH-pyrim.). 13C NMR: ꢁ = 22.76; 25.49; 48.02;
106.68; 159.46; 163.22; 163.73. MS: 169 (M + 1). Anal. Calcd
for C H N OS: C, 49.98; H, 4.79; N, 16.65; S, 19.06; found: C,
7
8
2
[9] M. S. K. Youssef, R. A. Ahmed, M. S. Abbady, S. A. Abdel-
Mohsen, and A. A. Omar, “Reactions of 4-(2-aminothiazole-
4-yl)-3-methyl-5-oxo-1-phenyl-2-pyrazoline. Synthesis of thia-
zolo[3,2-a]pyrimidine and imidazo[2,1-b]thiazole derivatives,”
49.81; H, 4.65; N, 16.33; S, 18.80.
4. Conclusions
¨
Monatshefe fur Chemie, vol. 139, no. 5, pp. 553–559, 2008.
6-Methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) can
be obtained with high yield (90%) on treatment of acetoacetic
acid ethyl ester with thiourea in sodium methylate. When the
latter reacts with 3-chloro-pentane-2,4-dione, the substitu-
tion occurs at sulfur atom (2) and the further regioselective
cyclization with good yields afforded 2-acetyl-3,7-dimethyl-
5H-thiazolo[3,2-a]pyrimidin-5-one. is three-step synthe-
sis is convenient and efficient and can be used for the synthe-
ses of different biologically active thiazolo[3,2-a]pyrimidine
derivatives.
e preliminary biological assay indicates that investi-
gated biheterocyclic system derivatives show growth stim-
ulant activity and can be of interest to obtain new growth
regulators.
[10] A.-E.-G. Amr, S. S. Maigali, and M. M. Abdulla, “Microwave
assisted synthesis of some new thiazolopyrimidine, thiazolod-
ipyrimidine and thiazolopyrimidine derivatives with potential
¨
antioxidant and antimicrobial activity,” Monatshefe fur Chemie,
vol. 139, pp. 1409–1415, 2008.
[11] M. J. Solanki and M. M. Chavda, “Synthesis and antimi-
crobial activity of some novel derivatives of thiazolo[2,3-
b]dihydropyrimidine containing 4-pyrazolyl moiety,” Rasayan
Journal of Chemistry, vol. 4, no. 3, pp. 605–608, 2011.
[12] Q. Chen, X.-L. Zhu, L.-L. Jiang, Z.-M. Liu, and G.-F. Yang,
“Synthesis, antifungal activity and CoMFA analysis of novel
1,2,4-triazolo[1,5-a]pyrimidine derivatives,” European Journal of
Medicinal Chemistry, vol. 43, no. 3, pp. 595–603, 2008.
[13] V. Patel, “Synthesis, characterization and antifungal activity
of substituted ethyl 5,7- dimethyl-3-oxo-2,3-dihydro-5H-[1,3]-
thiazolo[3,2-a]pyrimidie-6-carboxylate derivatives,” Der Phar-
macia Sinica, vol. 4, no. 5, pp. 72–78, 2013.
Competing Interests
[14] M. Bansal, R. Kaur, and B. Kaur, “Synthesis and antifungal
evaluation of thiazolo[3,2-ꢔ]pyrimidine,” Journal of Applicable
Chemistry, vol. 2, no. 3, pp. 391–397, 2013.
e authors declare no conflict of interests.
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