Synthesis and density functional theory study of [1,2,3]triazolo[4,5-d][1,2,4] triazolo[4,3-A]pyrimidine derivatives: A novel heterocyclic system

Article abstract of DOI:10.3184/174751916X14743011878429

Several 3H-[1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-A]pyrimidine derivatives of a novel ring system have been synthesised. The initial substitution of the 4-Cl function of 2,4-dichloro-6-methylpyrimidin-5-Amine with benzylamine followed by treatment with

Full text of DOI:10.3184/174751916X14743011878429

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 OCTOBER, 633–636
RESEARCH PAPER 633
Synthesis and density functional theory study of [1,2,3]triazolo[4,5-d][1,2,4]
triazolo[4,3-a]pyrimidine derivatives: A novel heterocyclic system
Sarinasadat Mozafari, Ali Shiri*, Mehdi Bakavoli, Marzieh Akbarzadeh, Kayvan Saadat and
Yasaman Etemadi
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
Several 3H-[1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives of a novel ring system have been synthesised. The initial
substitution of the 4-Cl function of 2,4-dichloro-6-methylpyrimidin-5-amine with benzylamine followed by treatment with sodium nitrite
generated 3-benzyl-5-chloro-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine. Nucleophilic substitution of the 5-Cl moiety of the latter
compoundwithhydrazinehydrateandsubsequenttreatmentwithcarbondisulfideinboilingpyridinegave, quantitatively, thecorresponding
[
1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives. Density functional theory (DFT) studies were also performed to reveal
1
regioselectivity of the ring closure via Gauge-Independent Atomic Orbital (GIAO) H NMR calculations. The WP04 method was used as the
DFT code to yield accurate chemical shift values. Theoretical results correlated well with the expected regioisomer and aided assignment
of the final structure.
Keywords: [1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine, heterocyclisation, DFT, NMR spectroscopy
Nitrogen-containing heterocycles are important targets for
synthetic endeavours because of their exciting biological
propertiesandtheirrolesaspharmacophoresofmanybiologically
the synthesis of 7-substituted-3-benzyl-9-methyl-3H-[1,2,3]
triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives
6a–f as members of a new heterocyclic system and theoretical
1
active compounds. Among them, triazolopyrimidines with a
evaluation of their ring closure orientation.
bridgehead nitrogen are interesting purine analogues as they
possess significant therapeutic properties for pharmacological
applications. They have been reported to be versatile ligands
in which their coordination compounds can be considered as
model systems for the metal–ligand interactions observed
Results and discussion
2
The starting material, 2,4-dichloro-6-methylpyrimidin-5-amine
1, can be easily obtained from the reduction of 2,4-dichloro-
6-methyl-5-nitropyrimidine with iron powder in boiling
acetic acid according to our previously published method.
Treatment of compound 1 with benzylamine in boiling i-PrOH
3
–6
29
in biological systems.
,2,3-triazolopyrimidines are interesting purine analogues,
they possess significant therapeutic and pharmacological
More specifically, as 1,2,4- and
1
and subsequent diazotisation in the presence of NaNO /HCl
2
2
,7–10
11
applications in their basic structures
antitumor, anti-inflammatory, antibacterial, antifungal
and antimalarial properties.
including anticancer,
afforded 3-benzyl-5-chloro-7-methyl-3H-[1,2,3]triazolo[4,5-d]
pyrimidine 3 in quantitative yield (Scheme 1). The selective
nucleophilic displacement of the C-4 chlorine atom in compound
12
13
14
15
16
Additionally, these compounds have been used as important
and useful starting materials for the synthesis of other fused
1 by NH -containing nucleophiles proceeded according to our
2
3
0,31
similar, previously reported, procedure.
This phenomenon
17–19
heterocyclic systems.
Some recently published protocols for
can be explained via the repulsive interaction between the
lone pairs on the pyrimidine ring nitrogen atoms and the NH2
nucleophile, with the result that substitution of the Cl-2 function
requires a higher temperature than the Cl-4 substituent. The
assembling this bicyclic system have been accomplished through
a one-pot multicomponent reaction using substituted aromatic
aldehydes, malononitrile and 3-amino-1,2,4-triazole catalysed
2
0
by boric acid in aqueous micellar conditions, oxidative
cyclisation of 4-amino-6-arylidene(heteroarylmethylidene)
2-hydrazino-substituted derivative 4 was synthesised by
treating compound 3 with hydrazine hydrate in boiling EtOH.
The spectral and microanalytical data of the entire range of
synthesised compounds 2–4 have been summarised in the
experimental section.
hydrazinyl-1,3,5-triazin-2-ones with Pb(OAc)4 via
a
21
Dimroth-type rearrangement,
diaminopyrimidines with NaNO /HCl and cyclisation of
treatment of chloro-5,6-
2
2
2
diethyl 2,4,6-trifluorophenylmalonate with 3-amino-1,2,4-
triazole.
While investigating the treatment of compound 4 with CS2
in dry pyridine, as depicted in Scheme 2, to obtain either the
11
Regarding these points, and due to our interest in the synthesis
of various fused heterocyclic derivatives with a pyrimidine
corresponding
[1,2,4]triazolo[4,3-a]pyrimidine-7(6H)-thione
isomeric 1-benzyl-4-methyl-1H-[1,2,3]triazolo[4,5-e][1,2,4]
3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d]
5
or the
2
3–28
core,
herein we wish to report a convenient method for
Ph
Ph
Ph
Cl
N
Cl
H
Cl
N
N
N
PhCH NH Cl
N
NH NaNO , HCl
N
N
N
H
N
N
2
2
2
2
4
H N
2
N
N
N
NH2
N
N
N
NH2
Me
Me
Me
Me
(1)
(2)
(3)
(4)
Scheme 1
*
Correspondent. E-mail: alishiri@um.ac.ir

634 JOURNAL OF CHEMICAL RESEARCH 2016
Ph
Ph
Ph
H
5
N
3
N
N
N
N
N
N
N
N
N
N
CS2
RX
H N
2
N
HN
N
N
N
N
N
N
N
1
9
7
S
RS
Me
Me
Me
(4)
(5)
(6a-e)
6
6
6
6
a: R= CH3
CS2
b: R= C H5
2
c: R= n-C H7
3
d: R= n-C H9
S
SR
4
8
HN
N
N
6 N
6e: R= PhCH2
Ph
Ph
1
N
N
RX
N
N
N
N
N
N
N
N
3
4
Me
e
M
(5')
(6a-e)'
Scheme 2
triazolo[4,3-a]pyrimidine-8(7H)-thione 5' and its subsequent
like structures for 6a–e and phenanthrene-like structures for
(6a–e)'. In addition, the corresponding Gibbs free energy data
were extracted for the gas phase at 298 K and 1 atm. to evaluate
the thermodynamic stability of the regioisomers.
alkylation with various alkyl halides in the presence of Et N
3
in boiling CH CN, the regioselectivity of the cyclisation was
3
found to be ambiguous in these reactions. Therefore, the
evidence that confirmed which nitrogen atom available on the
1
Relative H chemical shifts for the model structures were
pyrimidine core was cyclised by CS and the outcome from
calculated as follows:
2
subsequent alkylation by the appropriate alkyl halide was
deduced via computational results and by comparing them with
the experimental data.
δI = σTMS – σi
(1)
where σ and σ
were the calculated isotropic magnetic
TMS
i
shielding tensors for the desired proton of the model and TMS,
All the newly synthesised compounds 6a–e and (6a–e)' have
been characterised via their physical, chemical and spectral
data. The IR spectrum of compound 5 or 5' displayed the
respectively. It should be mentioned that σ = 32.01 ppm
TMS
was obtained at the polarized continuum model (PCM)
(chloroform)/WP04/aug-cc-pVDZ//B3LYP/6-311+g(2d,p)
level of calculations.
–1
stretching vibration band of the NH group at 3100 cm which
1
was removed after alkylation. On the other hand, the H NMR
The chemical shifts of the two benzylic hydrogens on the
carbon attached to nitrogen N-3 in (6a–e)' or on nitrogen N-1 in
spectrum of either product 6b or 6b', as an example, showed
a triplet signal at 1.53 ppm with a coupling constant of 7.2 Hz
due to the methyl group of the ethyl moiety, a singlet peak at
(
6a–e)' are summarised in Table 1. It can be seen from the data
that if compounds (6a–e)' actually existed they would exhibit
a characteristic signal with a lower field (> 6 ppm) shift. The
hypothetical larger chemical shifts of the benzylic hydrogens in
models (6a–e)' belong to the protons that are located near to the
sulfur atom. The comparison of theoretical with experimental
chemical shifts indicated that the reaction goes forward to yield
compounds 6a–e as the final structures.
3
.29 ppm corresponding to the methyl group on the pyrimidine
ring, a quartet signal at 3.36 ppm for the methylene protons
of the ethyl group with a coupling constant of 7.2 Hz and two
multiplet signals at around 7.26–7.36 and 7.51–7.54 ppm due to
the phenyl group in the product. The C NMR spectrum of 6b
or 6b' also showed 12 signals at 13.9, 15.2, 25.8, 50.6, 128.7,
13
128.9, 129.2, 134.4, 142.9, 146.9, 155.8 and 172.5 ppm. The
Among the benzylic protons, H #2 of compounds 6a–e has the
best match with experimental values. The observed increasing
differences in calculated chemical shifts with experimental
values of H #1 in models 6a–e belong to the proton located
adjacent to nitrogen N-4.
From an energy viewpoint, all derivatives were checked
against each other to determine which structure was more
favourable thermodynamically. For this purpose, the calculated
sum of electronic energy and corrected Gibbs free energy of
models 6a–e were compared with their peer derivatives (6a–e)'.
mass spectrum displayed the molecular ion peak at m/z = 234
+
(
M ‏) related to the molecular formula of C H N S.
15 15 7
Further structural confirmations were made using two-
dimensional nuclear Overhauser effect spectroscopy (NOESY)
for compound 6b. The hydrogens of the methylene moiety of SEt
as a quartet at 3.37 ppm show interactions with the hydrogens of
the C-9 Me group as a singlet at 3.29 ppm, whilst the N-3 benzyl
protons are unaffected. These results indicate that the correct
structures of products 6a–e are those shown in Scheme 1.
Computational evaluations
The results showed that 6a, 6b, 6c, 6d and 6e are 2.50, 2.25, 1.68,
1
We decided to conduct a theoretical evaluation of the
H
−1
1
.85 and 1.33 kcal mol , respectively, more thermodynamically
NMR spectra via the Gauge-Independent Atomic Orbital
stable than their corresponding isomers (6a', 6b', 6c', 6d' and
e'). These data were obtained from frequency calculations in
the gas phase, 298 K and 1 atm., for models at the B3LYP/6-
11+g(2d,p) level of theory.
32
(
GIAO) method. Therefore, quantum calculations of NMR
6
were performed to indicate the direction of ring closure.
Accordingly, two main structures were presumed, anthracene-
3

JOURNAL OF CHEMICAL RESEARCH 2016 635
1
Table 1 Experimental and unscaled GIAO H NMR chemical shifts in
3-Benzyl-5-chloro-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (3)
ppm relative to TMS for benzylic protons (on carbon attached to nitrogen
N-3 of (6a–e)' or nitrogen N-4 of (6a–e') in PCM(chloroform)/WP04/aug-
cc-pvdz//B3LYP/6-311+g(2d,p)
4
To a stirring mixture of N -benzyl-2-chloro-6-methylpyridine-4,5-
diamine 2 (4 mmol, 1.0 g) and concentrated HCl (2 mL) solution in
water (2 mL), a solution of NaNO (8 mmol, 0.6 g) in water (3 mL)
2
Benzylic
Experimental
Δδ (ppm)
H
was added dropwise in an ice-water bath. After the completion of the
Compound
a
b
a
b
H #1 H #2 Benzylic Integration
H #1
0.03
0.32
0.02
0.31
0.02
0.44
0.05
0.44
0.18
0.50
H #2
reaction which was monitored by TLC using CHCl /MeOH (30:1),
3
water was added and the resulting precipitate was filtered off, washed
with water (2 × 20 mL) and recrystallised from EtOH. Yellow solid;
6
6
6
6
6
6
6
6
6
6
a
5.86 5.84
6.15 6.39
5.85 5.83
6.14 6.50
5.85 5.83
6.27 6.71
5.88 5.84
6.27 6.70
5.66 5.60
6.34 6.44
5.83
5.83
5.83
5.83
5.84
2
0.01
0.56
0.00
0.67
0.00
0.88
0.01
0.87
0.24
0.60
a'
b
1
yield 70%; m.p. 140–143 °C; H NMR (CDCl ): δ 3.03 (s, 3H, CH ),
3
3
5
.83 (s, 2H, CH N), 7.29–7.41 (m, 3H, Ar-H), 7.47–7.49 (m, 2H, Ar-
2
2
13
H); C NMR (CDCl ): δ 20.4, 50.8, 128.5, 128.8, 129.0, 134.0, 134.9,
3
b'
c
+
+
150.1, 158.5, 165.5; MS: m/z 259 (M ), 168 (M – C H ); Anal. calcd
7 7
2
for C H ClN : C, 55.50; H, 3.88; N, 26.97; found: C, 55.45; H, 3.85;
12 10 5
N, 26.94%.
c'
d
2.02
2
3-Benzyl-5-hydrazinyl-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (4)
To a solution of 3-benzyl-5-chloro-7-methyl-3H-[1,2,3]triazolo[4,5-d]
pyrimidine 3 (1 mmol, 0.3 g) in EtOH (5 mL), hydrazine hydrate
d'
e
(1 mL) was added and the solution was refluxed for 5 h. After
e'
completion of the reaction, the solution was cooled and the resulting
solid was filtered off, washed with water (2 × 20 mL) and recrystallised
a
b
Adjacent proton to nitrogen N-4 of 6a–e (see Scheme 2).
Adjacent proton to sulfur atom in (6a–e)'.
1
from EtOH. White solid; yield 85%; m.p. 140–142 °C; H NMR
(
7
4
CDCl ): δ 2.02 (s, 2H, NH ), 2.90 (s, 3H, CH ), 5.76 (s, 2H, CH N),
3 2 3 2
13
.30–7.43 (m, 5H, Ar-H), 8.20 (s, 1H, NH); C NMR (CDCl ): δ 25.8,
3
9.7, 128.1, 128.2, 128.7, 132.3, 135.2, 150.7, 158.2, 164.2; IR (KBr)
Conclusions
−1
nmax/cm : 3448, 3274, 3060, 3029, 2937, 1610, 1559, 1469, 1449; MS:
m/z 255 (M ), 164 (M – C H ); Anal. calcd for C H N : C, 56.46; H,
+
+
The chemical procedures outlined in this paper provided very
simple and straightforward routes to obtain various derivatives
of [1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine. The
compounds designed and synthesised were studied for their
true regiochemistry via theoretical calculations, and the results
showed that the cyclisation reaction proceeds in such a way as
to give the anthracene-like heterocycle. DFT calculations at
the PCM/WP04/aug-cc-pVDZ//B3LYP-6-311+g(2d,p) level of
theory were used to calculate the proton chemical shifts, and
compounds 6a–e correlated well with the experimental data in
comparison with models (6a–e)'. Moreover, the relative Gibbs
free energy revealed that compounds 6a–e are more favourable
thermodynamically than (6a–e)'. Further studies are in progress
to improve our knowledge of their biological activities.
7 7 12 13 7
5.13; N, 38.41; found: C, 56.40; H, 5.09; N, 38.37%.
3
-Benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]
pyrimidine-7(6H)-thione (5)
To a stirred solution of 3-benzyl-5-hydrazinyl-7-methyl-3H-[1,2,3]
triazolo[4,5-d]pyrimidine 4 (1 mmol, 0.3 g) in pyridine (5 mL), CS2
(
2 mmol, 0.12 mL) was added and the solution was heated under
reflux for 7 h. After completion of the reaction, which was monitored
by TLC using CHCl /MeOH (5:1), the solvent was removed under
3
reduced pressure. The resulting solid was washed with water (10 mL)
and recrystallised from EtOH. Pale brown powder; yield 76%; m.p.
1
2
20–222 °C; H NMR (CDCl ): δ 2.91 (s, 3H, CH ), 5.75 (s, 2H,
3
3
13
CH N), 7.31–7.44 (m, 5H, Ar-H), 7.66 (s, 1H, NH); C NMR (CDCl ):
2
3
δ 25.8, 49.7, 128.1, 128.2, 128.7, 132.3, 135.2, 150.7, 158.2, 164.2,
−
1
1
1
65.4; IR (KBr) nmax/cm : 3100, 3067, 3039, 2929, 1631, 1587, 1554,
+ +
498, 1452, 1432; MS: m/z 297 (M ), 206 (M – C H ); Anal. calcd for
Experimental
7 7
C H N S: C, 52.51; H, 3.73; N, 32.97; S, 10.78; found; C, 52.47; H,
13
11
7
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 for KBr disks and only noteworthy
absorptions are listed. The H NMR (300 MHz) and C NMR
75 MHz) spectra were recorded on a Bruker Avance DRX-400
3.69; N, 32.92, S, 10.69%.
Synthesis of [1,2,3]triazolo[4,5-d][1,2,4]triazolo[4,3-a]pyrimidine
(6a–e); general procedure
1
13
(
To a solution of compound 5 (1 mmol, 0.3 g) and an appropriate alkyl
Fourier Transform spectrometer. Chemical shifts are reported in ppm
downfield from tetramethylsilane (TMS) as 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
Microanalyzer.
halide (1 mmol) in CH CN (10 mL), Et N (1 mmol, 0.1 mL) was added
and the solution was refluxed for about 6 h. After completion of the
3
3
reaction, which was monitored by TLC using CHCl /MeOH (9:1), the
3
solvent was removed under reduced pressure. The resulting solid was
washed with water (2 × 10 mL) and recrystallised from EtOH.
7
-Methylthio-3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d]
4
N -Benzyl-2-chloro-6-methylpyrimidine-4,5-diamine (2)
[
1
5
1,2,4]triazolo[4,3-a]pyrimidine (6a): White solid; yield 70%; m.p.
40–143 °C; H NMR (CDCl ): δ 2.65 (s, 3H, CH ), 3.29 (s, 3H, CH S),
.83 (s, 2H, CH N), 7.31–7.36 (m, 3H, Ar-H), 7.50–7.55 (m, 2H, Ar-
H); C NMR (CDCl ): δ 15.6, 16.5, 38.8, 128.6, 128.7, 129.0, 130.6,
56.5, 165.9, 185.3; IR (KBr) n /cm : 3064, 3039, 2929, 1631, 1587,
554, 1498; MS: m/z 311 (M ), 192 (M – C H N ); Anal. calcd. for
To a stirred solution of 2,6-dichloro-4-methylpyrimidine-3-amine 1
10 mmol, 1.78 g) in i-PrOH (15 mL), benzylamine (10 mmol, 1.1 g)
was added and the resulting mixture was heated under reflux for 12 h.
After completion of the reaction, the solvent was concentrated and the
resulting precipitate was filtered, washed with water (2 × 20 mL) and
recrystallised from EtOAc and n-hexane. Yellow powder; yield 90%;
1
3
3
3
(
2
13
3
−1
1
1
max
+
+
7
7
2
C H N S: C, 54.00; H, 4.21; N, 31.49; S, 10.30; found: C, 53.95; H,
14
13
7
1
m.p. 160–162 °C; H NMR (CDCl ): δ 3.08 (s, 3H, CH ), 5.72 (s, 2H,
CH N), 7.31–7.39 (m, 3H, Ar-H), 7.46–7.48 (m, 2H, Ar-H); C NMR
4.18; N, 31.40; S, 10.23%.
7-Ethylthio-3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d][1,2,4]
triazolo[4,3-a]pyrimidine (6b): White solid; yield 65%; m.p.
130–134 °C; H NMR (CDCl ): δ 1.51 (t, J = 6.0 Hz, 3H, CH ), 3.29 (s,
3H, CH ), 3.37 (q, J = 6.0 Hz, 2H, CH ), 5.84 (s, 2H, CH N), 7.31–7.34
3 2 2
3
3
1
3
2
(
CDCl ): δ 20.2, 50.5, 128.4, 128.8, 129.1, 134.1, 134.8, 150.0, 158.3,
3
−1
1
1
1
65.2; IR (KBr) nmax/cm : 3434, 3359, 3297, 3258, 3056, 2925, 2872,
3
3
+
+
659, 1587, 1496, 1455; MS: m/z 249 (M ), 157 (M – C H ); Anal.
calcd for C H ClN : C, 57.95; H, 5.27; N, 22.53; found: C, 57.90; H,
.22; N, 22.48%.
7
7
13
(m, 3H, Ar-H), 7.50–7.55 (m, 2H, Ar-H); C NMR (CDCl ): δ 13.9,
15.2, 25.8, 50.6, 128.7, 128.9, 129.2, 134.4, 142.9, 146.9, 155.8, 172.5;
12
13
4
3
5

636 JOURNAL OF CHEMICAL RESEARCH 2016
−
1
IR (KBr) n /cm : 3035, 2970, 2921, 1632, 1589, 1552, 1492; MS: m/z
Received 25 May 2016; accepted 29 August 2016
Paper 1604115 doi: 10.3184/174751916X14743011878429
Published online: 27 September 2016
max
+
+
3
25 (M ), 234 (M – C H ); Anal. calcd for C H N S: C, 55.37; H,
7 7 15 15 7
4
.65; N, 30.13; S, 9.85; found: C, 55.46; H, 4.7; N, 29.98, S, 9.79%.
-Propylthio-3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d]
1,2,4]triazolo[4,3-a]pyrimidine (6c): White solid; yield 60%; m.p.
80–185 °C; H NMR (CDCl ): δ 1.09 (t, J = 7.2 Hz, 3H, CH ), 1.87
sextet, J = 7.2 Hz, 2H, CH ), 3.28 (s, 3H, CH ), 3.35 (q, J = 7.2 Hz, 2H,
CH S), 5.83 (s, 2H, CH N), 7.30–7.36 (m, 3H, Ar-H), 7.51–7.54 (m, 2H,
Ar-H); C NMR (CDCl ): δ 13.3, 13.9, 23.2, 33.3, 50.5, 128.7, 128.9,
29.2, 134.4, 142.0, 146.9, 155.8, 172.8; IR (KBr) nmax/cm : 3064,
027, 2962, 2929, 2876, 1629, 1588; 1550, 1496; MS: m/z 339 (M ),
7
[
1
References
1
1
C.F. Beyer, N. Zhang, R. Hernandez, D. Vitale, J. Lucas, T. Nguyen, C.
Discafani, S. Ayral-Kaloustian and J.J. Gibbons, Cancer Res., 2008, 68, 2292.
G. Fischer, Adv. Heterocycl. Chem., 2007, 95, 143.
M.A. Phillips, R. Gujjar, N.A. Malmquist, J. White, F. El Mazouni, J. Baldwin
and P.K. Rathod, J. Med. Chem., 2008, 51, 3649.
3
3
(
2
3
2
3
2
2
13
3
−1
1
3
3
4
5
R. Gujjar, A. Marwaha, F. El Mazouni, J. White, K.L. White, S. Creason,
D.M. Shackleford, J. Baldwin, W.N. Charman, F.S. Buckner, S. Charman, P.K.
Rathod and M.A. Phillips, J. Med. Chem., 2009, 52, 1864.
W. Yu, C. Goddard, E. Clearfield, C. Mills, T. Xiao, H. Guo, J.D. Morrey, N.E.
Motter, K. Zhao, T.M. Block, A. Cuconati and X. Xu, J. Med. Chem., 2011,
+
+
+
+
10 (M -C H ), 264 (M – C H S), 206 (M – C H N ); Anal. calcd
2 5 3 7 7 7 3
for C H N S: C, 56.62; H, 5.05; N, 28.89; S, 9.45: found: C, 56.57; H,
.01; N, 28.84; S, 9.39%.
-Butylthio-3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d]
1,2,4]triazolo[4,3-a]pyrimidine (6d): White solid; yield 80%;
m.p. 160–164 °C; H NMR (CDCl ): δ 0.97 (t, J = 7.5 Hz, 3H, CH ),
.48–1.56 (m, 2H, CH ), 1.77 (quint., J = 7.2 Hz, 2H, CH ), 3.29 (s, 3H,
CH ), 3.35 (t, J = 7.5 Hz, 2H, CH S), 5.84 (s, 2H, CH N), 7.30–7.36
m, 3H, Ar-H), 7.50–7.54 (m, 2H, Ar-H); C NMR (CDCl ): δ 13.6,
16
17
7
5
5
4, 5660.
J.M. Salas, M.A. Romero, M.P. Sánchez and M. Quirós, Coord. Chem. Rev.,
999, 193, 1119.
7
6
7
[
1
1
P. Molina, A. Arques, M .V . Vinader, J. Becher and K. Brondum, J. Org. Chem.,
1988, 53, 4654.
3
3
1
2
2
8
Y. Sato, Y. Shimoji, H. Fujita, H. Nishino, H. Mizuno, S. Kobayashi and S.
Kumakura, J. Med. Chem., 1980, 23, 927.
3
2
2
13
(
3
9
H. Ohnishi, K. Yamaguchi, S. Shimada, Y. Suzuki and A. Kumagai, Life Sci.,
1
1
3.9, 21.9, 31.1, 31.7, 50.5, 128.7, 128.9, 129.2, 134.4, 142.8, 146.9,
55.3, 155.8, 172.0; IR (KBr) nmax/cm : 3060, 3031, 2957, 2929, 2870,
631, 1587, 1552, 1496; MS: m/z 353 (M ), 262 (M – C H ), 234 (M –
1981, 28, 1641.
−1
10
T. Novinson, R. Springer, D.E. O’Brien, M.B. Scholten, J.P. Miller and R.K.
+
+
+
1
Robins, J. Med. Chem., 1982, 25, 420.
7
7
C H N ); Anal. calcd for C H N S: C, 57.77; H, 5.42; N, 27.74; S, 9.07;
11 N. Zhang, S. Ayral-Kaloustian, T. Nguyen, J. Afragola, R. Hernandez, J. Lucas,
7
7
2
17 19
7
J. Gibbons and C. Beyer, J. Med. Chem., 2007, 50, 319.
found: C, 57.71; H, 5.39; N, 27.70; S, 9.01%.
-Benzylthio-3-benzyl-9-methyl-3H-[1,2,3]triazolo[4,5-d]
1,2,4]triazolo[4,3-a]pyrimidine (6e): White solid; yield 69%; m.p.
12
X.-L. Zhao, Y.-F. Zhao, S.-C. Guo, H.-S. Song, D. Wang and P. Gong,
Molecules, 2007, 12, 1136.
7
[
1
5
13
H.M. Ashour, O.G. Shaaban, O.H. Rizk and I.M. El-Ashmawy, Eur. J. Med.
Chem., 2013, 62, 341.
1
74–180 °C; H NMR (CDCl ): δ 3.29 (s, 3H, CH ), 4.59 (s, 2H, CH S),
3
3
1
2
3
.84 (s, 2H, CH N), 7.31–7.55 (m, 10H, Ar-H); C NMR (CDCl ): δ
14 R. Kumar, R.R. Nair, S.S. Dhiman, J. Sharma and O. Prakash, Eur. J. Med.
Chem., 2009, 44, 2260.
15 Q. Chen, X.-L. Zhu, L.-L. Jiang, Z.-M. Liu and G.-F. Yang, Eur. J. Med. Chem.,
2
3
3
7.6, 38.5, 54.1, 128.1, 128.4, 128.7, 128.8, 128.9, 129.1, 129.2, 134.7,
−1
135.2, 135.8, 155.1, 164.8, 185.8; IR (KBr) nmax/cm : 3067, 3031, 2932,
2008, 43, 595.
+ +
2
074, 1631, 1586, 1551, 1490; MS: m/z 387 (M ), 296 (M – C H ), 264
7
7
16 A. Marwaha, J. White, F. El Mazouni, S.A. Creason, S. Kokkonda, F.S.
Buckner, S.A. Charman, M.A. Phillips and P.K. Rathod, J. Med. Chem., 2012,
55, 7425.
+
(
M – C H S); Anal. calcd for C H N S: C, 62.00; H, 4.42; N, 25.30;
7 7 20 17 7
S, 8.28; found: C, 61.94; H, 4.36; N, 25.24; S, 8.21%.
1
7
S. Boutaleb-Charki, C. Marín, C.R. Maldonado, M.J. Rosales, J. Urbano, R.
Guitierrez-Sánchez, M. Quirós, J.M. Salas and M. Sánchez-Moreno, Drug
Metab. Lett., 2009, 3, 35.
Computational details
All optimisation, frequency and NMR calculations were performed
with the Gaussian 09 Rev. A.01 package. All computational models
were geometrically optimised without any symmetric restriction by
33
18 G. Ruisi, L. Canfora, G. Bruno, A. Rotondo, T.F. Mastropietro, E.A. Debbia,
M.A. Girasolo and B. Megna, J. Organomet. Chem., 2010, 695, 546.
M.M.A. El-Gendy, M. Shaaban, K.A. Shaaban, A.M. El-Bondkly and H.
Laatsch, J. Antibiot. (Tokyo), 2008, 61, 149.
S. Fatma, P.K. Singh, P. Ankit, Shireen, M. Singh and J. Singh, Tetrahedron
Lett., 2013, 54, 6732.
19
3
4
using B3LYP DFT code and choosing the 6-311+g(2d,p) basis set for
all atoms. Cartesian coordinates of geometrically optimised models
are available in the supplementary information. Frequency calculations
were done at the same level of theory to make sure that optimised
models were in their local minimum energy as long as no imaginary
frequency was observed. In order to perform accurate and precise
20
21 A .V . Zavodskaya, V .V . Bakharev, V.E. Parfenov, A.A. Gidaspov, P.A.
Slepukhin, M.L. Isenov and O.S. Eltsov, Tetrahedron Lett., 2015, 56, 1103.
22
A. Gigante, M.-D. Canela, L. Delang, E.-M. Priego, M.-J. Camarasa, G. Querat,
J. Neyts, P. Leyssen and M.-J. Pérez-Pérez, J. Med. Chem., 2014, 57, 4000.
N. Noorolahian and A. Shiri, J. Chem. Res., 2015, 39, 609.
1
35
H NMR GIAO calculations, the WP04 method and aug-cc-pVDZ
as the basis set were used as reported by Jain et al. so that no further
23
24 S.-H. Mousavi, H. Atapour-Mashhad, M. Bakavoli, A. Shiri, M. Akbarzadeh
and Z. Tayarani-Najaran, Russ. J. Bioorganic Chem., 2015, 41, 201.
25 A. Karimian, H. Eshghi, M. Bakavoli, A. Shiri, M. Saadatmandzadeh, T.
Asghari and H. Moradi, J. Iran. Chem. Soc., 2015, 12, 1501.
3
6
scaling operation was necessary at this level of calculation. Also,
1
H NMR GIAO chemical shift calculations were performed via SCRF
3
7
with the PCM model to consider the solvent effect (chloroform).
Geometrical optimisation and the computation of isotropic magnetic
shielding tensors for TMS as reference were performed at the same
level of calculation.
26
A. Hazrathoseyni, S.M. Seyedi, A. Shiri and H. Eshghi, J. Chem. Res., 2015,
9, 148.
T. Akaberi, A. Shiri and S. Sheikhi-Mohammareh, J. Chem. Res., 2016, 40, 44.
3
27
28 A. Hazrathoseyni, S.M. Seyedi, H. Eshghi, A. Shiri, M. Saadatmandzadeh and
A.R. Berenji, J. Heterocycl. Chem., 2016, 53, 135.
Acknowledgements
29 M. Akbarzadeh, M. Bakavoli, H. Eshghi and A. Shiri, J. Heterocycl. Chem,
2015, 53, 832.
The authors gratefully acknowledge the Research Council
of Ferdowsi University of Mashhad for partial support of
this project (3/37984) and the High Performance Computing
Center of Ferdowsi University of Mashhad for carrying out the
computations.
3
0
M. Bakavoli, S.M. Seyedi, A. Shiri, S. Saberi, M. Gholami and H. Sadeghian,
J. Chem. Res., 2013, 37, 48.
31 T. Asghari, M. Bakavoli, M. Rahimizadeh, H. Eshghi, S. Saberi, A. Karimian,
F. Hadizadeh and M. Ghandadi, Chem. Biol. Drug Des., 2015, 85, 216.
3
2
K. Wolinski, J.F. Hinton and P. Pulay, J. Am. Chem. Soc., 1990, 112, 8251.
G.E.S.M.J. Frisch, G.W. Trucks, H.B. Schlegel, B.M.M.A. Robb, J.R.
Cheeseman, G. Scalmani, et al. Gaussian, Inc., Wallingford CT, “Gaussian 09,
Revision A.01.” Gaussian Inc., 2009.
33
Electronic supplementary information
1
13
34 A.D. Becke, J. Chem. Phys., 1993, 98, 5648.
K.W. Wiitala, T.R. Hoye and C.J. Cramer, J. Chem. Theory Comput., 2006,
, 1085.
R. Jain, T. Bally and P.R. Rablen, J. Org. Chem., 2009, 74, 4017.
37 J. Tomasi, B. Mennucci and R. Cammi, Chem. Rev., 2005, 105, 2999
H and C NMR data and NOESY spectra for 6b are given in
35
the electronic supplementary information which is available
through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
2
36