Synthesis, characterisation, and in vitro antibacterial evaluation of a new class of 2-substituted-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-A] pyrimidines

Article abstract of DOI:10.3184/174751916X14737838285904

The reaction of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with 4,5-dihydrothiazol-2-Amine in chloroform led to the formation of 2-chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-A]pyrimidine (3). The true structure of the target compound was confirmed by density functional theory calculations of condensed Fukui indices. The substitution of the 2-Cl function in compound 3 with different secondary amines yielded 2-substituted-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-A]pyrimidines in good yields. The assigned products were tested for their potential antibacterial activity and the results indicated that a few derivatives are valuable compounds with great potential to be used as antibacterial agents.

Full text of DOI:10.3184/174751916X14737838285904

6
00 RESEARCH PAPER
VOL. 40 OCTOBER, 600–603
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis, characterisation, and in vitro antibacterial evaluation of a new
class of 2-substituted-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]
pyrimidines
a
a
a
a
a
Yasaman Etemadi , Ali Shiri *, Hossein Eshghi , Marzieh Akbarzadeh , Kayvan Saadat , Sarinasadat
a
b
b
Mozafari , Hamid Beyzaei and Mohammadreza Moghaddam-Manesh
a
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
b
The reaction of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with 4,5-dihydrothiazol-2-amine in chloroform led to the formation of
-chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine (3). The true structure of the target compound was confirmed
2
by density functional theory calculations of condensed Fukui indices. The substitution of the 2-Cl function in compound 3 with different
secondary amines yielded 2-substituted-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]pyrimidines in good yields. The assigned
products were tested for their potential antibacterial activity and the results indicated that a few derivatives are valuable compounds with
great potential to be used as antibacterial agents.
Keywords: heterocyclisation, pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine, DFT, Fukui indices, antibacterial evaluation
Fused heterocycles containing thiazolopyrimidine and
pyrimidopyrimidine have been greatly investigated for several
the related pyrimido[4,5-d]pyrimidine derivatives after the
elimination of dimethylamine from the cycloadducts as well as
1
17
biological and medicinal activities, including antimalarial, A
the oxidative aromatisation.
2
A
2
3
4
adenosine receptor antagonist, antifungal, antitubercular ,
In view of these observations and in continuation of our study
5
6
7
18–21
antimicrobial, antiallergic, antihypertensive, and anticancer
on fused pyrimidines,
we have undertaken the synthesis
8
agent. In addition they are phosphodiesterase and dihydrofolate
of some new derivatives of pyrimido[4,5-d]thiazolo[3,2-a]
pyrimidine and tested their antibacterial activity.
9
reductase inhibitors.
General synthetic methods for the synthesis of
thiazolopyrimidines involve the reaction of the commercially
Results and discussion
available
isothiocyanates or the reaction of ethyl 4-(3-methoxyphenyl)-
-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
4,6-dichloro-5-aminopyrimidine
with
Initially, 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine
1 as precursor was prepared through the treatment of
6-methyluracil and formaldehyde in 10% aqueous NaOH
10
6
11
with bromomalononitrile in the presence of strong base. In
another study, the treatment of 1,3,4-trihydropyrimidine-2-
thione with chloroacetic acid in the presence of anhydrous
NaOAc in refluxing HOAc provided the corresponding
and subsequent chlorination in boiling POCl according to
3
2
2
our previously published method. Compound 1 reacted
with 4,5-dihydrothiazol-2-amine 2 as a binucleophile at −5
to 0 °C in CHCl to give 2-chloro-4-methyl-7,8-dihydro-5H-
3
12
thiazolo[3,2-a]pyrimidines.
pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine
3
(Scheme 1).
The synthesis of pyrimidopyrimidines as the other
significant heterocyclic moiety has been reported via a one-
pot three component heterocyclisation of 5-aminopyrimidine
The formation of compound 3 proceeds through a combined
nucleophilic substitution and an addition–elimination reaction
involving the nitrogen atoms in 4,5-dihydrothiazol-2-amine
followed by elimination of two molecules of HCl.
13
with formamide in the presence of PBr3. Also, reaction of
-cyanopurines with O-benzylhydroxylamine or isoniazide
9
The evidence that confirmed that the chloromethyl group on
the pyrimidine 1 was initially substituted by nucleophiles rather
14,15
resulted in the formation of pyrimidopyrimidines.
Recently, an efficient method for the synthesis of aromatic
-acylhydrazido-8-arylaminopyrimidopyrimidine derivatives
2
2
than the 4-Cl group was obtained from previous work. Since
there are two different nitrogen atoms in reactant 1 that are
candidates to act as a nucleophile, two regioisomeric products
are possible. To shed light and dispel this ambiguity, condensed
4
16
has been published. The [4 + 2] cycloaddition reactions of
-[(dimethylamino)methylene]amino uracil with various in
situ-generated imine glyoxylates or imine oxides provided
6
2
3
Fukui indices were computed.
1
10
N
9
S
2
H N
'
4
Cl
N
R N
2
N
N
Cl
N
Cl
S
1
2
2
CHCl3
R NH
2
S
5
N
Cl
N
N
N
N
N
o
1
3
EtOH, reflux
'
N
-5 to 0 C, 7h
5
7
Me
5
3
Me
Me
1
2
3
4a-f
Entry
R N-
4a
4b
4c
4d
4e
Me N
4f
2
N
O
N
N
Me
N
N
Ph N
Scheme 1
*
Correspondent. E-mail: alishiri@um.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2016 601
1
To calculate condensed Fukui indices for the previously
geometrical optimised structures of 1 and 2, three single-point
calculations with +1, −1 and 0 net charges were performed
proposed structures. The H NMR spectrum of product 4b, as
an example, showed two singlet signals at 2.17 and 4.45 ppm due
to the methyl group on the pyrimidine ring and the methylene
(
B3LYP/6-311++g(2d,p)). These calculations were performed
protons of the CH N unit, respectively and a triplet signal at
2
using UCA-FUKUI software and the corresponding equations
3.32 ppm indicating the presence of methylene protons from the
2
4
–
available in the literature. In condensed Fukui equations, f ,
CH S moiety. The signals of hydrogens from the morpholine ring
k
2
+
0
f , f , and are nucleophilicity, electrophilicity and radical
and CH N also appeared around δ 3.72–3.85. Further structural
2
k
k
confirmations were made using two-dimensional COSY and
attack susceptibility of atom k in the molecule, respectively.
Table 1 presents the Fukui indices for the assigned atoms in
electrophile 1 and nucleophile 2.
1
1
NOESY techniques. H-5 as a singlet at 4.45 ppm shows a H– H
COSY correlation with H-7 as a multiplet at 3.72–3.77 ppm,
+
1
1
The results showed a magnitude of 0.0157 and 0.0524 for fC
which, in turn, shows a H– H COSY correlation with the
methyl group at 2.17 ppm. The 2D-NOESY measurements of
4b also revealed interactions between the protons of the H-5
with H-7 and methyl hydrogens. Such interactions would not
be detected for the alternatively oriented thiazoline ring isomer.
These data clearly indicate the correct structures of products
4a–f illustrated in Scheme 1.
−
for C4 and C5′ in compound 1, respectively. Also fN values for
N3 and N2′ in compound 2 were obtained as 0.2963 and 0.1149,
respectively. The results revealed greater electrophilicity of
C5′ in 1 and more nucleophilicity of N3 in 2. Therefore, the
condensed Fukui calculations suggested that compound 3 is
formed in the way that the endocyclic nitrogen of compound
2
1
was first reacted with the exocyclic carbon of compound
to generate the C(sp3)–N bond in the depicted structure of
Antibacterial evaluations
A preliminary screening of the synthesised compounds 4a–f,
as well as the three reference drugs, amikacin, ceftriaxone
and cefazolin, were evaluated in vitro against a panel of
eleven Gram-positive and ten Gram-negative bacteria using
the agar well diffusion method. Only the results of the six
bacteria that have inhibition diameters more than 11 mm are
reported in Table 2 and the other ones were inactive. All tested
compounds except 4a and 4f (derivatives that have pyrrolidine
and N-phenylpiperazine moieties) were found to be weak or
moderate agents against a few pathogenic microorganisms.
Later on, the minimum concentrations required for inhibiting
the growth (minimum inhibitory concentration) and killing the
compound 3.
1
The H NMR spectrum of compound 3 showed two singlet
signals at 2.16 and 4.42 ppm due to protons from the methyl
and C-5 methylene groups, respectively. Also, the appearance
of two triplet signals at 3.30 and 3.70 ppm for the hydrogens
of the thiazoline ring confirmed the constitution of compound
2
5
3. The IR spectrum of compound 3 also revealed the presence
−1
of stretching vibrations of C–H bands at 2856 and 2956 cm
and disappearance of the NH vibrations of the precursor. In
the mass spectrum, the molecular ion peak was observed at m/z
2
2
41, which corresponds to the desired molecular formula of 3.
Further investigation was carried out via nucleophilic
−1
bacteria (minimum bactericidal concentration) in μg mL were
determined for the assigned compounds as well as for the three
reference drugs using the serial dilution technique. The results
are presented in Table 2.
substitution of the 2-Cl substituent with various secondary
amines to produce substituted derivatives 4a–f of the new
heterocyclic ring in good to excellent yields. All the physical,
chemical and spectral data were in agreement with the newly
2
6
Many studies have reported antibacterial activities of
derivatives. The structure–activity relationships based on
2
7–29
Table 1 Condensed Fukui indices for C4 and C5′ of 1 and N3 and N2′
of 2
the literature results
indicated that fused pyrimidines,
especially thiazolopyrimidine derivatives, have antibacterial
activity. The obtained results indicated that the compounds
bearing 2-(piperidin-1-yl) 4c and 2-(4-methylpiperidin-1-yl) 4d
substituents show the highest sensitivity against Streptococcus
equinus and Streptococcus pneumonia, respectively, compared
with ceftriaxone and cefazolin as reference drugs, which may
be due to the lipophilicity increase of the moiety, which has
enhanced the pharmacological activity. The other compounds
–
+
0
Compound
Atom
fk
fk
fk
C4
C5′
N3
0.0006
−0.0438
0.2963
0.1149
0.0157
0.0524
0.0180
0.0461
0.0082
0.0043
0.1572
0.0805
1
2
N2′
Table 2 Antibacterial activities of synthesised derivatives 4a–f against some bacteria
Gram positive bacteria
Gram negative bacteria
Proteus vulgaris
(PTCC 1079)
MIC MBC
Bacillus cereus
Bacillus subtilis subsp. Streptococcus equinus Streptococcus pneumonia Enterococcus faecalis
Spizizenii (PTCC 1023) (PTCC 1445) (PTCC 1240) (PTCC 1778)
Compound
(
PTCC 1665)
a
b
c
IZD
MIC MBC
IZD
–
–
–
12
MIC MBC IZD
MIC MBC IZD MIC MBC IZD MIC MBC IZD
d
4a
4b
4c
4d
4e
4f
–
13
–
82
–
164
164
82
–
–
–
–
–
–
–
–
14
–
–
5
–
–
–
–
10
–
–
–
–
–
16
10.5
13
–
–
–
10
5
10
–
–
–
20
10
20
–
–
12
–
14
–
–
40
–
40
–
–
82
–
–
–
11
–
–
10
–
–
20
16.5 82
12 40
15.5 82
20
40
82
–
–
–
–
82
–
12
–
20
–
40
–
163
–
12.5 40
–
–
–
–
–
–
–
–
–
–
–
Amikacin
Ceftriaxone
Cefazolin
IZD = inhibition zone diameter (mm).
MIC = minimum inhibitory concentration (μg mL ).
20
–
–
0.5
–
–
0.5 17
4
8
0.5
1
12
8
21
1
8
16
2
16
64
17.5
–
–
1
–
–
1
–
–
–
18.5
18.5
–
1
2
–
2
8
22.5
–
8.5
4
–
8
4
–
32
–
–
25.5 0.25
34 0.5
a
b
c
d
−1
−1
MBC = minimum bactericidal concentration (μg mL ).
The IZD, MIC, and MBC of compounds with IZD <11 (mm) were not reported.

6
02 JOURNAL OF CHEMICAL RESEARCH 2016
were found to exhibit slight to moderate activities against the
mentioned organisms.
Completion of the reaction was monitored by TLC using n-hexane-
EtOAc (15:10). The solvent was evaporated under reduced pressure,
water was added and the product was filtered off.
Conclusion
4-Methyl-2-(pyrrolidin-1-yl)-7,8-dihydro-5H-pyrimido[4,5-d]
thiazolo[3,2-a]pyrimidine (4a): Light yellow solid; m.p. 346–348 °C;
The objective of the present study was to synthesise, assign the
regiochemistry of heterocyclisation and investigate the antibacterial
activity of new pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine
derivatives. The newly tested synthesised compounds 4c and 4d
were found to exhibit essentially equipotent antibacterial activity
against Streptococcus equinus and Streptococcus pneumonia,
respectively, compared with ceftriaxone and cefazolin as reference
drugs. The results suggest that pyrimido[4,5-d]thiazolo[3,2-a]
pyrimidine derivatives emerge as valuable compounds with great
potential to be used as antibacterial agents. Hence, it is concluded
that there is a promising scope for further development in this field.
−1
yield 69%; IR (KBr disc) (ν cm ): 2998, 2956, 2860, 1666, 1567;
max
1
H NMR (300 MHz, CDCl ): δ 1.94 (t, J = 6.6 Hz, 4H, CH ), 2.15
3
2
(
s, 3H, CH ), 3.29 (t, J = 7.2 Hz, 2H, CH S), 3.57 (t, J = 6.6 Hz, 4H,
3
2
13
CH N), 3.71 (t, J = 7.2 Hz, 2H, CH N), 4.41 (s, 2H, CH N); C NMR
2
2
2
(
2
75 MHz, CDCl ): δ 171.2, 162.3, 160.8, 160.7, 96.0, 54.0, 46.6, 45.8,
3
+
5.6, 25.5, 20.7; MS m/z: 275 (M ), 247, 205, 70, 28. Anal. calcd for
C H N S: C, 56.70; H, 6.22; N, 25.43; S, 11.64; found: C, 56.62; H,
13
17
5
6
.18; N, 25.38; S, 11.57%.
-(4-Methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]
pyrimidin-2-yl)morpholine (4b): White solid; m.p. 236–238 °C; yield
4
−1
1
7
(
3
0%; IR (KBr disc) (νmax cm ): 2921, 2855, 1575, 1422, 745; H NMR
300 MHz, CDCl ): δ 2.17 (s, 3H, CH ), 3.32 (t, J = 7.2Hz, 2H, CH S),
3
3
2
Experimental
13
.74–3.81 (m, 10H, CH O, CH N), 4.45 (s, 2H, CH N); C NMR (75
2
2
2
Melting points were recorded on an Electrothermal type 9100 melting point
apparatus. The IR spectra were obtained on an Avatar 370 FTIR Thermo
Nicolet spectrophotometer and only noteworthy absorptions are listed. The
H NMR (300 MHz) and the C NMR (75 MHz) spectra were recorded
on a Bruker Avance DRX-300 Fourier transform spectrometer. Chemical
shifts were reported in ppm downfield from TMS as the internal standard.
The mass spectra were scanned on a Varian Mat CH-7 instrument at 70
eV. Elemental analyses were performed on a Thermo Finnigan Flash EA
MHz, CDCl ): δ 20.8, 25.7, 44.3, 45.8, 54.0, 66.9, 97.2, 161.1, 161.8,
3
+
162.3, 171.7; MS m/z: 291 (M ), 205, 177, 42, 29. Anal. calcd for
C H N OS: C, 53.59; H, 5.88; N, 24.04; S, 11.00; found: C, 53.52; H,
13
17
5
1
13
5.81; N, 23.98; S, 11.09%.
4-Methyl-2-(piperidin-1-yl)-7,8-dihydro-5H-pyrimido[4,5-d]
thiazolo[3,2-a]pyrimidine (4c): Cream-coloured solid; m.p 189–191 °C;
−
1
yield 90%; IR (KBr disc) (ν cm ): 2930, 2850, 1576, 1542, 1421,
max
1
1303, 1182, 747; H NMR (300 MHz, CDCl ): δ 1.57–1.65 (m, 6H, CH ),
2.15 (s, 3H, CH ), 3.31 (t, J = 7.2 Hz, 2H, CH S), 3.65 (t, J = 7.2 Hz, 2H,
3 2
3
2
1
112 microanalyser. Geometry optimisation and frequency calculations
30
+
were carried out with the Gaussian 09 package. B3LYP density functional
CH N), 3.69–3.79 (m, 4H, CH ), 4.42 (s, 2H, CH N); MS m/z: 289 (M ),
2
2
2
31
theory code was utilised for all calculations along the 6-311++g(2d,p)
basis set applied to all atoms, with no symmetrical restriction for 1 and 2
input structures. No imaginary frequency was observed in frequency
calculations on geometrically optimised 1 and 2 models to ensure that they
located at their true local minimum of energy. All optimised coordination
for 1 and 2 are available in the Electronic Supplementary Information.
Solutions of all derivatives and antibiotics were prepared in DMSO and
double-distilled water. All tests were repeated three times and the results
were expressed as the average of three independent experiments. Gram-
negative and Gram-positive bacterial strains were prepared from Iranian
Research Organization for Science and Technology (IROST). All bacteria
were cultured on nutrient agar (HiMedia, India) and incubated for 24 h at
205, 178, 124, 84, 54, 28. Anal. calcd for C H N S: C, 58.10; H, 6.62; N,
14 19 5
24.20; S, 11.08; found: C, 58.05; H, 6.57; N, 24.14; S, 11.01%.
4-Methyl-2- (4-methylpiperidin-1-yl) -7,8 - dihydro-5 H-
pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine (4d): White solid; m.p.
−1
128–130 °C; yield 60%; IR (KBr disc) (ν cm ): 3002, 2949, 2918,
max
1
2859, 1572, 1544, 1423, 1357, 970, 790; H NMR (300 MHz, CDCl ):
3
δ 0.96 (d, J = 6.0 Hz, 3H, CH ), 1.08–1.20 (m, 2H, CH ), 1.57–1.69
3
2
(m, 3H, CH, CH ), 2.14 (s, 3H, CH ), 2.78 (td, J = 11.4 Hz, 1.5 Hz, 2H,
2
3
CH S), 3.30 (t, J = 7.2 Hz, 2H, CH N), 3.71 (t, J = 7.2 Hz, 2H, CH N),
2
2
2
13
4.41 (s, 2H, CH ), 4.79 (d, J = 12.9 Hz, 2H, CH N); C NMR (75 MHz,
2
2
CDCl ): δ 171.2, 161.9, 161.0, 96.1, 45.9, 31.4, 44.1, 34.1, 20.9, 25.6,
3
+
22.0: MS m/z: 303 (M ), 271, 204, 178, 93, 69, 56, 42, 29. Anal. calcd
37 °C under normal atmospheric air, except Streptococcus equinus and
for C H N S: C, 59.38; H, 6.98; N, 23.08; S, 10.57; found: C, 59.31; H,
15
21
5
Streptococcus pneumoniae, which were incubated in an atmosphere of 5%
6.92; N, 23.01; S, 10.49%.
CO . Finally, a bacterial suspension with concentration of 0.5 McFarland
4-Methyl-2- (4-methylpiperazin-1-yl) -7,8 - dihydro-5H-
pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine (4e): Light yellow solid;
2
8
−1
(1.5 × 10 CFU mL ) in Müller-Hinton broth (HiMedia, India) was
−1
obtained spectrophotometrically. Antibacterial activities were tested
m.p. 260–262 °C (dec.); yield 70%; IR (KBr disc) (ν cm ): 2920,
max
25,26
1
according the literature procedures.
2851, 1568, 1530, 1417, 1374, 1259, 758; H NMR (300 MHz, CDCl ):
3
δ 2.16 (s, 3H, CH ), 2.35 (s, 3H, CH ), 2.47 (t, 4H, J = 5.1 Hz, CH N),
3
3
2
2
-Chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]
3
.31 (t, 2H, J = 7.2 Hz, CH S), 3.73 (t, 2H, J = 7.2 Hz, CH N), 3.87 (t, 4H,
2
2
pyrimidine (3)
13
J = 4.8 Hz, CH N), 4.44 (s, 2H, CH N); C NMR (75 MHz, CDCl ): δ
2
2
3
To a magnetically stirred solution of 2,4-dichloro-5-(chloromethyl)-6-
methylpyrimidine, compound 1 (0.21 g, 1 mmol) and 4,5-dihydrothiazol-
1
66.8, 157.1, 156.3, 92.1, 49.2, 24.9, 41.1, 38.8, 20.9, 16.1; MS m/z: 304
+
(
M ), 277, 204, 148, 71, 57, 29. Anal. calcd for C H N S: C, 55.24; H,
14 20 6
2-amine 2 (0.11 g, 1 mmol), which was cooled in ice diisopropylethylamine
6
.62; N, 27.61; S, 10.53; found: C, 55.19; H, 6.56; N, 27.57; S, 10.47%.
-Methyl-2- (4-phenylpiperazin-1-yl) -7,8 - dihydro-5H-
pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine (4f): White solid; m.p.
(DIPEA) (0.4 g, 3 mmol), was added dropwise. Then the mixture was
4
stirred at 0° C for 7 h. The progress of the reaction was monitored by TLC
using chloroform-methanol (30:3). The solvent was evaporated under
reduced pressure, water was added and the residue was filtered off to give
compound 3 as: White solid; m.p. 170–172 °C; yield 50%; IR (KBr disc)
−1
2
1
3
02–204 °C; yield 60%; IR (KBr disc) (ν cm ): 2929, 2852, 1566,
max
1
537, 1443, 1233, 1156, 757; H NMR (300 MHz, CDCl ): δ 2.18 (s,
H, CH ), 3.22 (t, 4H, CH N), 3.32 (t, 2H, CH S), 3.65–3.80 (m, 6H,
3
−1
1
3
2
2
(
2
νmax cm ): 2956, 2856, 1565, 1534, 1468; H NMR (400 MHz, CDCl ): δ
3
CH N), 4.45 (s, 2H, CH N), 6.89 (t, J = 7.2 Hz, 1H, phenyl ring), 6.98
2
2
.16 (s, 3H, CH ), 3.30 (t, J = 7.3 Hz, 2H, CH S), 3.70 (t, J = 7.3 Hz, 2H,
3
2
(d, 2H, J = 7.8 Hz, phenyl ring), 7.29 (t, 2H, J = 7.8 Hz, phenyl ring);
+
CH N), 4.42 (s, 2H, CH N); MS m/z: 241 (M ), 211, 137, 77, 28. Anal. calcd
for C H ClN S: C, 44.91; H, 3.77; Cl, 14.73; N, 23.28; S, 13.32; found: C,
4
13
2
2
C NMR (75 MHz, CDCl ): δ 171.6, 161.8, 161.1, 129.1, 151.5, 119.8,
3
9
9
4
116.4, 97.1, 49.4, 25.7, 45.8, 43.7; MS m/z: 366 (M ), 244, 205, 146, 119,
+
4.85; H, 3.71; N, 23.19; S, 13.24%.
1
06, 76, 60, 41. Anal. calcd for C H N S: C, 62.27; H, 6.05; N, 22.93;
19 22 6
Synthesis of pyrimido[4,5-d]thiazolo[3,2-a]pyrimidines (4a–f);
S, 8.75; found: C, 62.23; H, 5.98; N, 22.87; S, 8.69%.
general procedure
Electronic Supplementary Information
To a mixture of 2-chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]
1
1
thiazolo[3,2-a]pyrimidine
0.11 g, 1 mmol) in dry ethanol (10 mL), the appropriate alkyl halide
1.1 mmol) was added and the solution was heated under reflux for 5 h.
3
(0.24 g,
1
mmol) and Et N
The NMR spectra of all new compounds, as well as H– H
COSY and NOESY spectra of 4b, are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
3
(
(

JOURNAL OF CHEMICAL RESEARCH 2016 603
1
6
A. Rocha, A.H. Bacelar, J. Fernandes, M.F. Proenca and M.A. Carvalho,
Synlett, 2014, 25, 343.
D. Prajapati, M. Gohain and A.J. Thakur, Bioorg. Med. Chem. Lett., 2006,
Received 1 May 2016; accepted 11 August 2016
Paper 1604081 doi: 10.3184/174751916X14737838285904
Published online: 23 September 2016
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