Synthesis of novel triazoles bearing 1,2,4-oxadiazole and phenylsulfonyl groups by 1,3-dipolar cycloaddition of some organic azides and their biological activities

Article abstract of DOI:10.3906/kim-1309-59

1,3-Dipolar cycloaddition of 5-azidomethyl-3-p-substituted phenyl-1,2,4-oxadiazoles to phenyl vinyl sulfone and bismaleimide gives rise straightforwardly to 1-((3-(p-substituted) phenyl-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2,3-triazoles and bisdihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H)-diones. The structures of the new cycloadducts were elucidated by means of IR, NMR (¹H, ¹³C, 2D), mass spectra, and physical characteristics (mp and R_fvalues). In addition, anticancer activities of the cycloadducts against MCF-7 cells were also investigated.

Full text of DOI:10.3906/kim-1309-59

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 739 – 755
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http://journals.tubitak.gov.tr/chem/
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c
⃝ TUBITAK
doi:10.3906/kim-1309-59
Research Article
Synthesis of novel triazoles bearing 1,2,4-oxadiazole and phenylsulfonyl groups by
1,3-dipolar cycloaddition of some organic azides and their biological activities
Ya¸sar DURUST1,∗, Hamza KARAKUS¸1, Muhsine Zeynep YAVUZ2,
¨
¨
2
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Ali Ak¸cahan GEPDIREMEN
1
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Department of Chemistry, Abant Izzet Baysal University, Bolu, Turkey
2
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Department of Medical Pharmacology, School of Medicine, Abant Izzet Baysal University, Bolu, Turkey
Received: 24.09.2013
•
Accepted: 13.02.2014
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Published Online: 15.08.2014
•
Printed: 12.09.2014
Abstract: 1,3-Dipolar cycloaddition of 5-azidomethyl-3-p-substituted phenyl-1,2,4-oxadiazoles to phenyl vinyl sulfone
and bismaleimide gives rise straightforwardly to 1-((3-(p-substituted) phenyl-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsul-
fonyl)-4,5-dihydro-1H -1,2,3-triazoles and bisdihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H )-diones. The structures of
the new cycloadducts were elucidated by means of IR, NMR (1 H, 13 C, 2D), mass spectra, and physical characteristics
(mp and Rf values). In addition, anticancer activities of the cycloadducts against MCF-7 cells were also investigated.
Key words: Azide, 1,3-dipolar cycloaddition, 1,2,4-oxadiazole, 1,2,3-triazole, pyrrole, anticancer activity
1. Introduction
Organic azides have recently been playing a significant role in the preparation of heterocyclic scaffolds of
triazoles. They have potency to undergo a variety of organic reactions and are important components in click
chemistry.1−16 They received considerable attention in the 1950s and 1960s in industrial applications such as
rubber, polymers, dyes, plastics technology, and especially in pharmacological usages.
Some examples are azidothymidine (zidovudine), an azidonucleoside (in the treatment of AIDS), azapride
(dopamine antagonist), azidamfenicol (for the treatment of bacterial infections in eyes), and azidomorphine
(analgesic, sedative) (Figure 1).17−24
Furthermore, heterocyclic compounds carrying 1,2,4-oxadiazole units are also of pharmaceutical impor-
tance and some of them have been found to be active against cancer cells and various types of tumors and
to inhibit enzymes like tyrosine kinase and monoamine oxidase. These compounds are also effective as mus-
carinic agonists, histamine H3 antagonists, and antiinflammatory agents. Heterocycles bearing 1,2,4-oxadiazole
moiety have also been assayed as heterocyclic amide and ester bioisosteres in the construction of new peptide
mimics and dipeptidomimetics.25−28 Two recently reported antimycobacterium tuberculosis agents containing
a 1,2,4-oxadiazole ring are shown below (Figure 2).29,30
Heterocyclic compounds containing 1,2,3- and 1,2,4-triazole rings have found increasing attention in
organic syntheses, biochemistry, and medicinal chemistry research due to their activity as antifungal and
anticonvulsant agents including being popular mimics in designing anticancer molecules (Figure 3).31−39
∗Correspondence: yasardurust@ibu.edu.tr
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Figure 1. Some important organic azides.
Figure 2. Some important 1,2,4-oxadiazoles.
Sulfones are known as an important class of compounds and various sulfone containing heterocycles
have been shown to possess diversified bioactivities such as antibacterial, antimalarial, anthelmintic, antilepral,
antineoplastic, antiinflammatory, and antidiabetic activities.40
In reference to the reasons mentioned above and our ongoing interest in 1,3-dipolar cycloaddition reactions
of the various types of ylides,41 1,2,4-oxadiazolyl substituted azides,42 and phenyl vinyl sulfone,43 and due to
very infrequent studies on the cycloaddition reactions between organic azides with dipolarophiles such as phenyl
vinyl sulfone and bismaleimide, we have focused on the synthesis of a series of pyrrolotriazole derivatives carrying
1,2,4-oxadiazole and phenylsulfonyl groups and their biological activities.
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Figure 3. Some important triazoles.
2. Results and discussion
2.1. Chemistry
To the best of our knowledge, there are a number of examples of cycloaddition reactions of organic azides
with electron-deficient alkenes, but those with organic azides (3a–k) bearing a 1,2,4-oxadiazole ring have not
been reported previously. The synthetic sequence of the preparation of the target cycloadducts is shown below
(Scheme 1). The exact structures of the novel cycloadducts 4a–k were identified by IR, NMR (1 H, 13 C, COSY,
NOESY, HMBC, and HSQC), mass spectra (low and high resolution), mp, and Rf characteristics. In the
IR spectra, the disappearance of the N=N=N absorption of the corresponding starting azides 3a–k at around
2100–2200 cm−1 and the appearance of the symmetric (1160–1120 cm−1) and asymmetric (1300-1350 cm−1
)
stretching absorptions of the sulfone group are evidence for 4-(phenylsulfonyl)-4,5-dihydro-[1,2,3]triazoles 4a–k.
In the 1 H NMR spectra of these compounds, the relevant H-atoms labeled as Ha , Hb , Hc , Hd , and He
in Figure 4 exhibited different splitting patterns.
Figure 4. Aliphatic protons of 4a–k.
The Ha proton, which has been found most deshielded due to the electron-withdrawing phenylsulfonyl
group, appeared as a doublet of doublets induced by vicinal Hb and Hc protons, approximately at around 5.80
ppm with J = 12.5, 7.9 Hz. Two doublets at around 5.30 and 5.20 ppm with J = 17.0 Hz can be attributed to
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the geminal Hd and He (AB system) protons. However, when compounds 4j and 4k were recorded in DMSO-d6
they gave a singlet proton resonance signal corresponding to 2 hydrogens. An interesting splitting pattern was
observed for geminal Hb and Hc protons at around 4.0 ppm with J = 12.0 Hz (Figure 5).
Scheme 1. Synthesis of oxadiazolylmethyltriazoles carrying phenylsulfone.
Figure 5. 1 H NMR spectrum of 4a.
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As for 13 C NMR assignments, iminic carbons of the oxadiazole ring resonated at around 173 (C-3 carbon
of oxadiazole) and 168 ppm (C-5 carbon of oxadiazole). The carbon atom of the triazole ring, which is attached
to the phenyl sulfonyl group, arose at around 95 ppm. The CH2 group of the triazole ring and the bridge CH2
resonate at around 45 and 44 ppm, respectively. From the HMBC and HSQC spectra, it can be seen that Ha
is attached to the carbon atom bearing the phenyl sulfone group and Hb and Hc protons belong to the triazole
CH2 group (Figures 6 and 7).
Figure 6. Partial HMBC spectrum of 4b.
Figure 7. Partial HSQC spectrum of 4b.
In the electron impact mass spectra of the cycloadducts 4a–k, molecular ions (M+) were not observed.
The major peaks with the relatively intense abundances of these cycloadducts appeared as [M–N2 ]+ , which
can be considered as aziridine radical cations. These are most likely generated by the loss of N2 from the
molecules (Scheme 2). These fragments appeared mostly as base peaks. There are also peaks related to the
PhSO2 extrusion from the molecular ion with low abundances.
Scheme 2. Mass spectral fragmentation of 4a–k.
As the second part of this work, we synthesized bis pyrrolo[3,4-d]- triazolediones 5 by the 1,3-dipolar
cycloaddition of organic azides 3 to 4,4’-methylene bis(N -phenyl maleimide) as another electron-deficient
alkene (Scheme 3). Thus, 10 new compounds were obtained and their structures were identified by spec-
troscopic/physical data. 5d (p-tolyl substituted cycloadduct) cannot be obtained by the conducted synthetic
procedure as a material of sufficient purity.
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Scheme 3. Synthesis of bistriazolopyrrolidines carrying oxadiazole moiety.
In the IR spectra of these compounds, strong absorptions appeared at around 1715 cm−1 related to the
C=O groups, which originated from bismaleimide. The 1 H NMR spectra show the bridge protons 3a–3a’ at
around 4.80 ppm as a doublet, 6a–6a’ appeared at around 5.90 ppm as a doublet, and the CH2 group between
oxadiazole and triazole rings appeared as a singlet at around 5.60 ppm; the one between 2 Ph rings resonated
at around 4.0 ppm (Figure 8).
Figure 8. Aliphatic proton signals of 5b.
2.2. Anticancer activity assay
4,5-Dihydro-1H -1,2,3-triazoles (4a–k) carrying phenylsulfonyl and oxadiazolylmethyl groups and bisdihydropyr-
rolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H)-diones (5a–k) carrying oxadiazolylmethyl groups were screened in vitro
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for anticancer activity against human breast cancer cell lines, MCF-7, at a concentration of 1 × 10−3 M and
the results are summarized below (Tables 1–3), indicating that among the phenylsulfonyl substituted triazoles
4a and 4d exhibited much higher activities against breast cancer cells (MCF-7). MCF-7 cells were maintained
in Dulbeccos’s Modified Eagle’s Medium (DMEM) F-12 (Invitrogen) supplemented with 10 % (v/v) fetal bovine
serum (FBS) (Invitrogen) and 1% antibiotic-antimycotic (penicillin streptomycin amphotericin B, Panbiotech).
Table 1. Cytotoxic activities of 4a–k against MCF-7 cellsa .
Compd
R
IC50 (M)
Anticancer activity (% growth at a
concentration of 1 × 10−3 M.
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Cl
Br
Me
F
I
MeO
MeS
CF3
NO2
NMe2
7.2 × 10−4 b 34.0 ꢀ 7.5
77.0 ꢀ 4.7
47.6 ꢀ 5.7
2.5 × 10−4 b 40.5 ꢀ 4.8
66.3 ꢀ 1.2
51.4 ꢀ 1.3
95.2 ꢀ 10.0
74.2 ꢀ 6.3
64.5 ꢀ 3.5
4j
4k
> 100
> 100
a Compounds tested in triplicate, data expressed as mean value ꢀ SD of 3 independent experiments. b 50% growth
inhibition as determined by MTT assay.
Table 2. Cytotoxic activities of 4a–k against MCF-7 cells (WST-1 assay)a .
Compd
R
Anticancer activity (% growth at a
concentration of 1 × 10−3 M)
31.7 ꢀ 3.8
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Cl
Br
Me
F
I
MeO
MeS
CF3
NO2
72.0 ꢀ 2.6
57.8 ꢀ 1.4
45.7 ꢀ 12.5
79.7 ꢀ 7.1
54.3 ꢀ 3.6
80.0 ꢀ 4.4
49.3 ꢀ 5.5
68.4 ꢀ 6.9
4j
4k
> 100
NMe2 > 100
a Compounds tested in triplicate, data expressed as mean value ꢀ SD of 3 independent experiments.
Except for the doses of 1 × 10−3 and 5 × 10−4 M, the ratio of DMSO was less than 5 per thousand.
Doses were compared to controls containing the same amount of DMSO. The MCF-7 cells were then placed into
96-well plates (20,000 cells per well in 100?µL of DMEM F-12 with 10% heat-inactivated fetal calf serum and
1% antibiotic-antimycotic). After the cells adhered to the wells, different doses of the compounds were exposed
to the cells for 24 h. After 24 h of incubation at 37 ◦ C and in 5% CO2 atmosphere, MTT measurement
was conducted. MTT (Roche) solution (5 mL of MTT; (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
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bromide) labeling reagent (1×), 5 mg/mL in phosphate buffered saline) providing the final concentration 1/10
was added to all samples. Afterwards, 100 µL of solubilization solution (10% SDS in 0.01 M HCl) was added to
each well, and the plate was incubated overnight at 37 ◦ C. The optical densities of the wells were measured at a
wavelength of 570 nm with reference of 690 nm using an ELISA microplate reader (Thermo Scientific Multiskan
FC).44 The results were calibrated with optical density measured without cells in the wells.
Table 3. Cytotoxic activities of 5a–k against MCF-7 cellsa .
Compd
R
IC50 (M)
Anticancer activity (% growth at a
concentration of 1 × 10−3 M)
100.0 ꢀ 3.4
5a
5b
5c
5e
5f
5g
5h
5i
H
Cl
Br
F
2.5 × 10−4 b 39.4 ꢀ 4.2
4.3 × 10−4 b 26.3 ꢀ 3.6
4.8 × 10−4 b 20.5 ꢀ 0.6
1.7 × 10−4 b 41.9 ꢀ 4.1
2.6 × 10−4 b 26.5 ꢀ 1.9
1.7 × 10−4 b 33.3 ꢀ 1.7
6.0 × 10−4 b 45.3 ꢀ 2.1
4.9 × 10−4 b 34.0 ꢀ 1.9
> 100
I
MeO
MeS
CF3
NO2
NMe2
5j
5k
a Compounds tested in triplicate, data expressed as mean value ꢀ SD of 3 independent experiments. b 50% growth
inhibition as determined by MTT assay.
2.3. WST-1 assay
MCF-7 cells were seeded at a concentration of 20,000 cells/well in 100 µL of DMEM F-12 (Invitrogen) with
10% heat-inactivated fetal bovine serum (Invitrogen) and 1% antibiotic-antimycotic (penicillin streptomycin
amphotericin B, Panbiotech). After the treatment of the cells with the compounds, they were incubated for 24
h. Then 10 µL of WST-1 (Roche-Cell Proliferation Reagent WST-1) was added to each well and incubated for
4 h at 37 ◦ C and in the presence of 5% CO2 atmosphere. Wells were measured at a wavelength of 450 nm with
using an ELISA microplate reader (Thermo Scientific Multiskan FC) (Table 3).45
When we take a look at the inhibitory values obtained from the MTT assay for compounds 5a–k, we see
that the better activity results are obtained from the MeO, I, NO2 , CF3 , Cl, and F substituted cycloadducts.
Among them, fluorine substituted bisdihydropyrrolotriazoledione 5e showed the best activity against MCF-7
cells (Table 3).
3. Experimental
3.1. General
All reactions were carried out under argon in dried solvents. All reagents were purchased from Merck (Germany)
and Alfa-Aesar (Germany) and used without purification. 1 H, 13 C, and 2D-NMR spectra were recorded on
Bruker and Varian (400 MHz for 1 H; 100 MHz for 13 C) spectrometers; δ in ppm relative to Me4 Si as internal
standard, J in Hz. IR spectra were recorded on a Shimadzu FTIR 8400-S instrument;?in cm−1 . Mass spectra
were run on a Waters 2695 Alliance Micromass ZQ LC/MS instrument; in m/z (rel. %). High resolution
mass measurements were performed on a Waters Synapt MS instrument. Melting points were determined on
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a Meltemp apparatus and are uncorrected. Flash column chromatography was performed on silica gel (Merck,
230–400 mesh ASTM). TLC was done using silica gel precoated plates with fluorescent indicator (Merck 5735). A
Chromatotron 7924T rotary TLC apparatus (T-Squared Technology, Inc. San Bruno, CA, USA) was utilized for
further separation and purifications. The stain solutions of permanganate and iodine were used for visualization
of the TLC spots. Compounds 1, 2, and 3 were synthesized according to methods described previously.42,46
3.1.1. Typical procedure for the preparation of 1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-4-(pheny-
lsulfonyl)-4,5-dihydro-1H-1,2,3-triazole (4a)
A mixture of phenyl vinyl sulfone (0.087 g, 0.504 mmol) and 5-(azidomethyl)-3-phenyl-1,2,4-oxadiazole 3a (0.100
g, 0.500 mmol) was stirred in benzene (25 mL) and the mixture was heated under reflux for 2 days. The reaction
was monitored by TLC. The reaction mixture was concentrated in vacuo, and the crude residue was purified
by flash column chromatography (n-hexane/ethyl acetate; 2:1) to give 4a as a white solid (0.083 g, 45%); mp
120–122 ◦ C. Rf : 0.52 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1)vmax 3064, 1597, 1573 (C=N), 1477,
1446, 1309 (SO2 -asym), 1153 (SO2 -sym), 742. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d,J = 9.5 Hz, 2H), 8.00
(d,J = 8.0 Hz, 2H), 7.56 (m, 6H), 5.79 (dd,J = 12.5, 7.8 Hz, 1H, CH-SO2), 5.31 (d, J = 17.0 Hz, 1H), 5.07
(d,J = 17.0 Hz, 1H), 4.08 (dd,J = 11.6, 7.8 Hz, 1H, CH2 -triazole), 3.82 (t,J = 12.0 Hz, 1H, CH2 -triazole).13
C
NMR (100 MHz, CDCl3) δ 172.8 (C=N) 168.2 (C=N), 137.2, 135.5, 134.3, 131.1, 129.1, 129.0, 128.7, 128.4,
127.6, 127.4, 127.0, 125.5, 94.6, (C-SO2), 44.7 (CH2 -triazole), 44.2 (CH2). LC-MS (70 eV) (m/z, %) = 342
(M+ - N2 , 100), 278 (32), 200 (15), 172 (53), 121 (27). HRMS (TOF MS ES+): Measured; 392.0781 Calculated
for C17 H15 N5 O3 S + Na; 392.0793.
3.1.2. 1-((3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2,
3-triazole (4b)
White solid (0.141 g, 70%); mp 125–126 ◦ C. Rf : 0.53 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax
3061, 1597, 1566 (C=N), 1416, 1410, 1309 (SO2 -asym), 1153 (SO2 -sym), 742. 1 H NMR (400 MHz, CDCl3) δ
8.01 (t, J = 7.5 Hz, 4H), 7.73 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 5.78 (dd,
J = 12.5, 7.8 Hz, 1H, CH-SO2), 5.29 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 17.0 Hz, 1H), 4.10 (dd, J = 13.9, 10.7
Hz, 1H, CH2 -triazole), 3.80 (t, J = 12.0 Hz, 1H, CH2 -triazole). 13 C NMR (100 MHz, CDCl3) δ 174.6 (C=N)
168.8 (C=N), 137.9, 136.1, 134.8, 129.7, 129.6, 129.4, 129.2, 128.8, 128.7, 128.4, 124.5, 125.2, 95.7, (C-SO2),
45.3 (CH2 -triazole), 44.9 (CH2). LC-MS (70 eV) (m/z, %) = 375 (M+ - N2 , 65), 312 (53), 206 (100), 171 (11).
HRMS (TOF MS ES+): Measured; 426.0395; Calculated for C17 H14 N5 O3 SCl + Na; 426.0404.
3.1.3. 1-((3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2,
3-triazole (4c)
Light yellow solid (0.067 g, 42%); mp 158–160 ◦ C. Rf : 0.49 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1
)
vmax 2955, 1595, 1566 (C=N), 1446, 1408, 1346 (SO2 -asym), 1155 (SO2 -sym), 840, 738. 1 H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H),
7.61 (t, J = 7.2 Hz, 2H), 5.75 (dd, J = 12.5, 7.9 Hz, 1H, CH-SO2), 5.30 (d, J = 17.0 Hz, 1H), 5.07 (d, J = 17.0
Hz, 1H), 4.07 (dd, J = 11.5, 7.9 Hz, 1H, CH2 -triazole), 3.80 (t, J = 12.0 Hz, 1H, CH2 -triazole). 13 C NMR (100
MHz, CDCl3) δ 174.6 (C=N), 168.9 (C=N), 136.8, 135.6, 134.8, 133.1, 130.3, 130.0, 129.8, 128.8, 128.2, 128.0,
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127.0, 125.7, 95.7, (C-SO2), 45.5 (CH2 -triazole), 44.9 (CH2). LC-MS (70 eV) (m/z, %) = 451 (M+ , 100),
417 (11), 282 (10), 226 (13). HRMS (TOF MS ES+): Measured; 448.0079; Calculated for C17 H14 N5 O3 BrS;
448.0079.
3.1.4. 4-(Phenylsulfonyl)-1-((3-p-tolyl-1,2,4-oxadiazol-5-yl)methyl)-4,5-dihydro-1H-1,2,3-triazole
(4d)
Light yellow solid (0.093 g, 48%); mp 152–154 ◦ C. Rf : 0.48 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1
)
vmax 2980, 1593, 1570 (C=N), 1448, 1343 (SO2 -asym), 1153 (SO2 -sym), 829, 742. 1 H NMR (400 MHz,
CDCl3) δ 8.00–7.95 (m, 3H), 7.80 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 6.9 Hz, 2H), 7.30
(d, J = 7.9 Hz, 2H), 5.79 (dd, J = 12.5, 7.7 Hz, 1H, CH-SO2), 5.28 (d, J = 17.0 Hz, 1H), 5.05 (d, J = 17.0 Hz,
1H), 4.06 (dd, J = 11.6, 7.7 Hz, 1H, CH2 -triazole), 3.81 (t, J = 12.1 Hz, 1H, CH2 -triazole), 2.45 (s, 3H). 13 C
NMR (100 MHz, CDCl3) δ 173.1 (C=N), 171.2, 168.6 (C=N), 142.0, 141.9, 135.9, 134.7, 129.6, 129.5, 129.2,
128.3, 127.4, 127.3, 123.1, 95.1 (C-SO2), 45.2 (CH2 -triazole), 44.8 (CH2), 21.6 (CH3). LC-MS (70 eV) (m/z,
%) = 356 (M+ - N2 , 100), 242 (22), 214 (16), 186 (8). HRMS (TOF MS ES−): Measured; 406.0959; Calculated
for C18 H17 N5 O3 NaS; 406.0950.
3.1.5. 1-((3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2, 3-
triazole (4e)
Yellow solid (0.059 g, 30%); mp 120–122 ◦ C. Rf : 0.61 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax
2926, 1597, 1546 (C=N), 1448, 1419, 1325 (SO2 -asym), 1153 (SO2 -sym), 854. 1 H NMR (400 MHz, CDCl3) δ
8.06 (dd, J = 8.4, 5.6 Hz, 2H), 7.97 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H),
7.32 (t, J = 3.0 Hz, 1H), 7.17 (t, J = 8.6 Hz, 2H), 5.77 (dd, J = 12.4, 4.0 Hz, 1H, CH-SO2), 5.27 (d, J =
17.2 Hz, 1H), 5.06 (d, J = 17.2 Hz, 1H), 4.06 (dd, J = 12.2, 4.0 Hz, 1H, CH2 -triazole), 3.79 (t, J = 12.2 Hz,
1H, CH2 -triazole). 13 C NMR (100 MHz, CDCl3) δ 174.2, 173.7 (C=N), 168.0 (C=N), 165.0 (d, JCF = 250.7
Hz), 137.6, 136.2, 135.0, 134.0, 130.0, 129.9, 129.7, 129.5, 129.2, 128.6, 95.4 (C-SO2), 54.2 (CH2 -triazole), 45.5
(CH2). LC-MS (80 eV) (m/z, %) = 410 ([M+ - N2 +H], 100). HRMS (TOF MS ES+): Measured; 461.1874
Calculated for C18 H14 FN5 O3 S+H+Na; 461.1899.
3.1.6. 1-((3-(4-Iodophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2,3-
triazole (4f)
Light yellow solid (0.100 g, 40%); mp 119–121 ◦ C. Rf : 0.48 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1
)
vmax 2934, 1593, 1565 (C=N), 1458, 1400, 1316 (SO2 -asym), 1151 (SO2 -sym), 738. 1 H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H),
7.60 (dd, J = 15.8, 7.8 Hz, 2H), 5.76 (dd, J = 12.6, 7.8 Hz, 1H, CH-SO2), 5.27 (d, J = 17.2 Hz, 1H, CH2),
5.06 (d, J = 17.2 Hz, 1H, CH2), 4.05 (dd, J = 11.8, 7.8 Hz, 1H, CH2 -triazole), 3.79 (t, J = 12.2 Hz, 1H, CH2 ,
triazole). 13 C NMR (100 MHz, CDCl3) δ 173.5 (C=N), 168.0 (C=N), 138.2, 135.9, 134.8, 134.5, 129.7, 129.5,
129.2, 128.9, 128.2, 128.0, 125.4, 99.4 (C-I), 95.1 (C-SO2), 49.4 (CH2 -triazole), 45.2 (CH2). LC-MS (80 eV)
(m/z, %) = 468 (M+ -N2 , 100), 496 (M+ +H, 60), 518 (36), 559 (44). HRMS (TOF MS ES+): Measured;
517.9758; Calculated for C17 H14 N5 O3 SI+ Na; 517.9760.
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3.1.7. 1-((3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,
2,3-triazole (4g)
Light yellow oil (0.102 g, 60%). Rf : 0.37 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax 2964, 1597,
1546 (C=N), 1481, 1425, 1309 (SO2 -asym), 1155 (SO2 -sym), 736. 1 H NMR (400 MHz, CDCl3) δ 8.01–7.97
(m, 4H), 7.70 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.00 (dd, J = 6.8 Hz, 2H), 5.77 (dd, J = 12.8,
7.6 Hz, 1H, CH-SO2), 5.26 (d, J = 16.8 Hz, 1H, CH2), 5.03 (d, J = 16.8 Hz, 1H, CH2), 4.05 (dd, J = 11.8,
7.8 Hz, 1H, CH2 -triazole), 3.87 (s, 3H, OCH3) 3.79 (t, J = 12.2 Hz, 1H, CH2 -triazole). 13 C NMR (100 MHz,
CDCl3) δ 173.1 (C=N), 168.5 (C=N), 162.4 (C-OCH3), 136.1 (2C), 135.0, 129.8 (2C), 129.5, 129.4, 118.6 (2C),
114.6 (2C), 95.3 (C-SO2), 55.6 (OCH3), 45.4 (CH2 -triazole), 45.0 (CH2). LC-MS (80 eV) (m/z, %) = 468
(M+ -N2 , 100), 496 (M+ +H, 60), 518 (36), 559 (44). HRMS (TOF MS ES+): Measured; 422.0912; Calculated
for C18 H17 N5 O4 S+Na; 422.0899.
3.1.8. 1-((3-(4-Methylthiophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-
1,2,3-triazole (4h)
Light yellow solid (0.092 g, 37%); mp 99–101 ◦ C. Rf : 0.45 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1
)
vmax 2924, 1599, 1570 (C=N), 1458, 1419, 1305 (SO2 -asym), 1151 (SO2 -sym), 740. 1 H NMR (400 MHz,
CDCl3) δ 7.96 (td, J = 9.2, 8.0, 1.2 Hz, 2H), 7.89–7.52 (m, 5H), 7.31 (d, J = 8.4 Hz, 2H), 5.77 (dd, J =
12.4, 7.6 Hz, 1H, CH-SO2), 5.25 (d, J = 17.2 Hz, 1H, CH2), 5.04 (d, J = 17.2 Hz, 1H, CH2), 4.05 (dd, J =
11.6, 7.8 Hz, 1H, CH2 -triazole), 3.78 (t, J = 12.4 Hz, 1H, CH2 -triazole), 2.53 (s, 3H, SCH3). 13 C NMR (100
MHz, CDCl3) δ 173.4 (C=N), 168.4 (C=N), 143.8, 138.2, 136.1, 134.9, 134.7, 134.0, 129.7, 129.4, 128.2, 127.9,
126.0, 125.9, 95.3 (C-SO2), 54.1 (CH2 -triazole), 49.7 (CH2), 15.2 (SCH3). LC-MS (80 eV) (m/z, %) = 388
(M+ - N2 , 100), 410 (37), 416 (M+ +H, 22), 451 (18), 479 (15). HRMS (TOF MS ES+): Measured; 438.0658;
Calculated for C18 H17 N5 O3 S2 + Na; 438.0671.
3.1.9. 1-((3-(4-Trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-
1H-1,2,3-triazole (4i)
Yellow solid (0.080 g, 34%); mp 104–106 ◦ C. Rf : 0.55 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax
2926, 1597, 1546 (C=N), 1448, 1419, 1325 (SO2 -asym), 1153 (SO2 -sym), 854. 1 H NMR (400 MHz, CDCl3) δ
8.05 (d, J = 8.8 Hz, 2H), 7.82–7.79 (m, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.31 (t, J =3.2 Hz, 3H), 5.77 (dd, J =
12.6, 7.8 Hz, 1H, CH-SO2), 5.30 (d, J = 17.2 Hz, 1H, CH2), 5.10 (d, J = 17.2 Hz, 1H, CH2), 4.10 (dd, J =
12.0, 4.0 Hz, 1H, CH2 -triazole), 3.80 (t, J = 12.2 Hz, 1H, CH2 -triazole). 13 C NMR (100 MHz, CDCl3) δ 174.7
(C=N), 167.3 (C=N), 137.6, 135.0, 134.0, 129.7, 129.5, 129.2, 128.6, 128.1, 127.9, 127.2, 126.1, 126.0, 110.0, 95.4
(C-SO2), 54.2 (CH2 -triazole), 52.2 (CH2). LC-MS (80 eV) (m/z, %) = 410 (M+ - N2 , 100), 435 (25), 473 (25),
576 (23), 593 (40). HRMS (TOF MS ES+): Measured; 461.1874; Calculated for C18 H14 F3 N5 O3 S+H+Na;
461.0745.
3.1.10. 1-((3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihydro-1H-1,2,
3-triazole (4j)
Yellow solid (0.133 g, 51%); mp 126–128 ◦ C. Rf : 0.37 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax
2941, 1581, 1529 (C=N), 1448, 1415, 1342 (SO2 -asym), 1153 (SO2 -sym), 854. 1 H NMR (400 MHz, DMSO-
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d6) δ 8.42 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 7.2 Hz, 2H), 7.77 (t, J = 7.0 Hz,
1H), 7.66 (t, J = 7.8 Hz, 2H), 6.35 (dd, J = 12.4, 7.2 Hz, 1H, CH-SO2), 5.39 (s, 2H, CH2), 3.90 (dd, J =
12.0, 7.6 Hz, 1H, CH2 -triazole), 3.73 (t, J = 12.6 Hz, 1H, CH2 -triazole). 13 C NMR (100 MHz, DMSO-d6) δ
176.1 (C=N), 166.7 (C=N), 149.9, 136.6, 135.2, 135.0, 134.8, 132.0, 129.8, 129.6, 129.2, 128.8, 128.7, 128.6,
128.2, 124.7, 124.4, 94.4 (C-SO2), 51.5 (CH2 -triazole), 45.0 (CH2 -oxadiazolylmethyl). LC-MS (80 eV) (m/z,
%) = 415 (M+H, 35], 387 (M+ - N2 , 100), 374 (47), 267 (60). HRMS (TOF MS ES+): Measured; 409.0584;
Calculated for C17 H14 N6 O5 S+Na; 409.0583.
3.1.11. 1-((3-(4-Dimethylaminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4-(phenylsulfonyl)-4,5-dihy-
dro-1H-1,2,3-triazole (4k)
Yellow solid (0.117 g, 57%); mp 102–104 ◦ C. Rf : 0.55 (n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax
2926, 1581, 1558 (C=N), 1489, 1431, 1344 (SO2 -asym), 1193 (SO2 -sym), 736. 1 H NMR (400 MHz, DMSO-
d6) δ 7.88 (dd, J = 8.4, 1.2 Hz, 1 H), 7.81–7.44 (m, 5 H), 6.80 (dt, J = 10.0, 5.2, 2.8 Hz, 3H), 6.33 (dd, J = 12.8,
7.6 Hz, 1H, CH-SO2), 5.28 (s, 2H, CH2), 3.88 (dd, J = 7.2, 4.4 Hz, 1H, CH2 -triazole), 3.70 (t, J = 12.6, Hz,
1H, CH2 -triazole), 3.00 (s, 6H, NMe2). 13 C NMR (100 MHz, DMSO-d6) δ 174.5 (C=N), 168.1 (C=N), 152.6,
136.6, 135.1, 134.3, 129.8, 129.6, 129.4, 128.6, 128.5, 128.2, 112.2, 112.1, 94.3 (C-SO2), 53.9 (CH2 -triazole),
51.7 (CH2 -oxadiazolylmethyl), 44.7 (N(CH3)2). LC-MS (80 eV) (m/z, %) = 413 [M+H, 25], 407 (58), 385 (M
- N2 , 100). HRMS (TOF MS ES+) Measured; 410.1681 Calculated for C19 H20 N6 O3 S-2H; 410.1695.
3.1.12. Typical procedure for the preparation of (3aS,6aR)-5-(4-((9S,10R)-4-((3aS,6aR)-4,6-Dioxo-
1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d][1,2,3] triazol-
5(1H)-yl)benzyl)phenyl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl) methyl)-1,6a-dihydropyrrolo[3,
4-d][1,2,3]triazole-4,6(3aH,5H)-dione (5a)
A mixture of 4,4-methylene bis(N-phenyl maleimide) (0.090 g, 0.250 mmol) and 5-(azidomethyl)-3-phenyl-1,2,4-
oxadiazole 3a (0.100 g, 0.500 mmol) was stirred in benzene (25 mL) and the mixture was heated under reflux
for 4 days. The reaction was monitored by TLC. The reaction mixture was concentrated in vacuo, and the
crude residue was washed with hexane to give 5a as a white solid (0.095 g, 50%); mp 172–174 ◦ C. Rf : 0.63
(n-hexane/ethyl acetate; 1:1). IR (KBr, cm−1) vmax 3074, 1718 (C=O), 1595, 1572 (C=N), 1348, 1192, 719.
1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 4 H), 7.44 (m, 6H), 7.13 (d, J = 10.1 Hz, 8H), 5.85 (d, J = 10.5 Hz, 2H),
5.50 (dd, J = 33.0, 17.4 Hz, 4H), 4.74 (d, J = 10.5 Hz, 2H), 3.94 (s, 2 H).13 C NMR (100 MHz, CDCl3) δ 175.3
(C=O), 171.3 (C=O), 170.0 (C=N), 168.2 (C=N), 141.3, 131.7, 129.8, 129.5, 129.2, 127.4, 126.8, 126.2, 83.8
(CH), 58.1 (CH), 44.5 (CH2), 29.5 (Ph-CH2 -Ph). HRMS (TOF MS ES+): Measured; 760.2262; Calculated
for C39 H28 N12 O6 ; 760.2255.
3.1.13. (3aS,6aR)-1-((3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(4-(4-((3aR,6aS)-1-((3-(4-
chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo[3,4-d][1,
2,3]triazol-5(1H )-yl)benzyl)phenyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-
dione (5b)
Yellow solid (0.155 g, 75%); mp 148–150 ◦ C. Rf : 0.63 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1) vmax
2958, 1716 (C=O), 1591, 1512 (C=N), 1379, 1186, 744. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.8
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Hz, 5H), 7.63 (m, 5H), 7.11 (d, J = 8.0 Hz, 6H), 5.92 (d, J = 11.2 Hz, 2H), 5.60 (s, 4 H), 4.77 (d, J =
11.2 Hz, 2H), 3.97 (d, J = 13.2 Hz, 2H).13 C NMR (100 MHz, DMSO-d6) δ 176.7 (C=O), 172.3 (C=O), 170.8
(C=N), 167.5 (C=N), 142.4, 142.1, 141.0, 137.2, 135.3, 130.2, 129.9, 129.5, 127.4, 125.3, 84.1 (CH), 58.7 (CH),
44.8 (CH2), 41.2 (Ph-CH2 -Ph). LC-MS (80 eV) (m/z, %) = 917 (100), 910 (81), 883 (63), 855 (56), 561 (93).
HRMS (TOF MS ES+): Measured; 828.1460; Calculated for C39 H26 Cl2 N12 O6 ; 828.1475.
3.1.14. (3aS,6aR)-1-((3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(4-(4-((3aR,6aS)-1-((3-
(4-bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo[3,4-d]
[1,2,3]triazol-5(1H )-yl)benzyl)phenyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,
5H )-dione (5c)
Yellow solid (0.130 g, 70%); mp 146–148 ◦ C. Rf : 0.60 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1) vmax
3039, 1720 (C=O), 1597, 1566 (C=N), 1381, 1184, 742. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 9.2
Hz, 4H), 7.90 (d, J = 8.4 Hz, 4H), 7.78 (m, 8H), 5.92 (d, J = 10.8 Hz, 2H), 5.60 (s, 4H), 4.77 (d, J = 11.2 Hz,
2H), 4.00 (d, J = 13.2 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ175.9 (C=O), 171.5 (C=O), 170.0 (C=N),
166.8 (C=N), 134.5, 132.4, 132.3, 129.1, 128.9, 126.6, 125.3, 124.9, 83.2 (CH), 57.9 (CH), 44.0 (CH2), 33.6
(Ph-CH2 -Ph). LC-MS (80 eV) (m/z, %) = 970 (100), 926 (81), 907 (57), 746 (31), 503 (55). HRMS (TOF MS
ES−): Measured; 889.0679 Calculated for C39 H25 N10 O6 Br2 [M-H-N2 ]; 889.0672.
3.1.15. (3aS,6aR)-1-((3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(4-(4-((3aR,6aS)-1-((3-
(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo[3,4-d]
[1,2,3]triazol-5(1H )-yl)benzyl)phenyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,
5H )-dione (5e)
Orange solid (0.157 g, 79%); mp 142–144 ◦ C. Rf : 0.40 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1) vmax
2985, 1720 (C=O), 1579, 1514 (C=N), 1381, 1186, 750. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (m, 6 H), 7.35
(m, 10 H), 5.93 (d, J = 11.2 Hz, 2 H), 5.60 (s, 4 H), 4.77 (d, J = 10.8 Hz, 2 H), 3.98 (d, J = 12.8 Hz, 4H).13
C
NMR (100 MHz, DMSO-d6) δ 175.8 (C=O), 171.5 (C=O), 170.1 (C=N), 166.7 (C=N), 163.9 (d, J = 248.4
Hz) (C-F), 141.2, 134.6, 129.6, 129.5, 129.1, 128.2, 126.6, 116.5, 116.3, 83.2 (CH), 57.9 (CH), 44.0 (CH2), 33.5
(Ph-CH2 -Ph). LC-MS (80 eV) (m/z, %) = 851 (100), 825 (67), 786 (82), 775 (44), 604 (73). HRMS (TOF MS
ES+): Measured; 795.1988; Calculated for C39 H25 N12 O6 F2 ; 795.1988.
3.1.16. (3aS,6aR)-1-((3-(4-Iodophenyl)-1,2,4-oxadiazol-5-yl)methyl)-5-(4-(4-((3aR,6aS)-1-((3-(4-
iodophenyl)-1,2,4-oxadiazol-5-yl)methyl)-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo[3,4-d][1,2,
3]triazol-5(1H )-yl)benzyl)phenyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-
dione (5f)
Yellow solid (0.100 g, 64%); mp 160–162 ◦ C. Rf : 0.55 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1) vmax
2956, 1720 (C=O), 1593, 1512 (C=N), 1402, 1182, 831. 1 H NMR (400 MHz, DMSO-d6) δ 7.96–7.70 (m, 6H),
7.40–7.05 (m, 10H), 5.91 (d, J = 10.4 Hz, 2H, 2×CH), 5.60 (s, 4H, 2×CH2), 5.19 (s, 2H, Ph-CH2 -Ph), 4.75
(d, J = 10.8 Hz, 2H, 2×CH).13 C NMR (100 MHz, DMSO-d6) δ 176.6, 176.4 (C=O), 172.2 (C=O), 170.7,
170.6 (C=N), 168.2, 167.8 (C=N), 138.9, 138.8, 135.3, 129.9, 129.8, 129.4, 127.5, 127.4, 125.7, 100.0, 99.8 (C-I),
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84.0 (CH), 58.6 (CH), 44.9 (CH2), 34.3 (Ph-CH2 -Ph). LC-MS (80 eV) (m/z, %) = 1019 (92), 959 (44), 904
(75), 687 (93), 391 (100). HRMS (TOF MS ES+): Measured; 1013.0266; Calculated for C39 H26 N12 O6 I2 ;
1013.0266.
3.1.17. (3aS,3a’S,6aR,6a’R)-5,5’-(4,4’-Methylenebis(4,1-phenylene))bis(1-((3-(4-methoxyphenyl)-
1,2,4-oxadiazol-5-yl)methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-dione)
(5g)
Light yellow solid (0.202 g, 78%); mp 154–156 ◦ C. Rf : 0.42 (n-hexane:ethyl acetate; 1:2). IR (KBr, cm−1
)
vmax 2937, 1720 (C=O), 1573, 1512 (C=N), 1381, 1255, 750. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J
= 11.6 Hz, 4H), 7.28–7.15 (m, 8H), 6.96 (d, J = 9.2 Hz, 4H), 5.85 (d, J = 10.8 Hz, 2H, 2×CH), 5.58 (d, J
= 18.0 Hz, 2H), 5.30 (d, J = 18.0 Hz, 2H), 4.78 (d, J = 10.8 Hz, 2H, 2×CH), 4.02 (d, J = 7.2 Hz, 2H,
Ph-CH2 -Ph), 3.86 (s, 6H, 2×OCH3).13 C NMR (100 MHz, DMSO-d6) δ 173.7 (C=O), 170.9 (C=O), 168.8
(C=N), 168.5 (C=N), 141.7, 134.4, 130.1, 129.9, 129.4, 129.0, 128.6, 126.5, 118.6, 114.6, 83.1, 57.3, 55.7 (CH2),
44.6 (Ph-CH2 -Ph). LC-MS (80 eV) (m/z, %) = 902 (66), 871 (100), 797 (M+ -N2 , 18), 594 (70). HRMS (TOF
MS ES+): Measured; 820.2470, Calculated for C41 H32 N12 O8 ; 820.2466.
3.1.18. (3aS,3a’S,6aR,6a’R)-5,5’-(4,4’-Methylenebis(4,1-phenylene))bis(1-((3-(4-(methylthio)
phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,
5H )-dione) (5h)
Light yellow solid (0.190 g, 92%); mp 147–149 ◦ C. Rf : 0.45 (n-hexane:ethyl acetate; 1:2). IR (KBr, cm−1
)
vmax 2976, 1716 (C=O), 1593, 1512 (C=N), 1379, 1184, 744. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.8
Hz, 2 H), 7.36 (s, 2 H), 7.26 (m, 12 H), 5.84 (d, J = 10.8 Hz, 2H, 2×CH), 5.58 (d, J = 17.6 Hz, 2H, CH2),
5.30 (d, J = 18.0 Hz, 2H, CH2), 4.76 (d, J = 10.8 Hz, 2H, 2×CH), 4.00 (d, J = 8.8 Hz, 2H, Ph-CH2 -Ph),
2.51 (s, 6H, 2×SCH3). 13 C NMR (100 MHz, CDCl3) δ 173.9 (C=O), 170.8 (C=O), 168.7 (C=N), 168.4
(C=N), 143.8, 142.0, 141.6, 140.2, 134.4, 130.0, 129.9, 129.0, 128.5, 128.0, 126.4, 126.3, 126.1, 126.0, 122.3,
83.1 (CH), 57.2 (CH), 44.5 (CH2), 41.2 (Ph-CH2 -Ph 15.3 (CH3 S). LC-MS (80 eV) (m/z, %) = 870 (100),
610 (73), 825 (M+ -N2 , 14), 875 (M+ +Na, 30). HRMS (TOF MS ES+): Measured; 853.2066; Calculated for
C41 H33 N12 O6 S2 , 853.2087.
3.1.19. (3aS,3a’S,6aR,6a’R)-5,5’-(4,4’-Methylenebis(4,1-phenylene))bis(1-((3-(4-(trifluoromethyl)
phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-
dione) (5i)
Light yellow solid (0.140 g, 63%); mp 158–160 ◦ C. Rf : 0.58 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1
)
vmax 2976, 1716 (C=O), 1595, 1512 (C=N), 1325, 1124, 758. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J
= 8.0 Hz, 4H), 7.93 (d, J = 8.0 Hz, 4H), 7.30–7.07 (m, 8H), 5.92 (d, J = 10.8 Hz, 2H, 2×CH), 5.63 (s, 4H,
2×CH2), 4.78 (d, J = 10.8 Hz, 2H, 2×CH), 3.94 (t, J = 20.2 Hz, 2H, Ph-CH2 -Ph). 13 C NMR (100 MHz,
DMSO-d6) δ 177.0 (C=O), 172.2 (C=O), 170.7 (C=N), 170.6, 167.3 (C=N), 142.1, 135.3, 132.3, 130.3, 130.0,
129.9, 129.8, 128.6, 127.4, 127.0, 84.0 (CH), 58.7 (CH), 44.9 (CH2), 41.1 (Ph-CH2 -Ph). LC-MS (80 eV) (m/z,
%) = 952 (100), 919 (M+ +Na, 93), 879 (M+ -N2 , 18), 707 (59). HRMS (TOF MS ES+): Measured; 896.2016;
Calculated for C41 H26 F6 N12 O6 , 896.2002.
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3.1.20. (3aS,3a’S,6aR,6a’R)-5,5’-(4,4’-Methylenebis(4,1-phenylene))bis(1-((3-(4-nitrophenyl)-1,2,
4-oxadiazol-5-yl)methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-dione) (5j)
Yellow solid (0.146 g, 69%); mp 148–150 ◦ C. Rf : 0.38 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1) vmax
3099, 1720 (C=O), 1581, 1514 (C=N), 1336, 1124, 723. 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (dd, J = 7.6,
2.4 Hz, 4 H), 8.23 (t, J = 1.6 Hz, 4 H), 7.30 (m, 4 H), 7.10 (t, J = 7.6 Hz, 4 H), 5.94 (d, J = 10.8 Hz, 2
H), 5.65 (s, 4 H), 4.79 (d, J = 10.8 Hz, 2 H), 3.95 (d, J = 17.6 Hz, 2 H).13 C NMR (100 MHz, DMSO-d6) δ
177.3 (C=O), 172.3 (C=O), 170.8 (C=N), 167.0 (C=N), 150.0, 142.2, 135.3, 132.2, 129.9, 129.2, 127.4, 125.2,
84.1 (CH), 58.7 (CH), 44.8 (CH2), 31.6 (CH2). LC-MS (80 eV) (m/z, %) = 905 (78), 851 (M+ +H, 39), 824
(M+ -N2 , 30), 610 (73), 413 (93), 229 (100). HRMS (TOF MS ES+): Measured; 850.2001; Calculated for
C39 H26 N14 O10 , 850.1956.
3.1.21. (3aS,3a’S,6aR,6a’R)-5,5’-(4,4’-Methylenebis(4,1-phenylene))bis(1-((3-(4-(dimethylamino)
phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH ,5H )-
dione) (5k)
Brown solid (0.131 g, 75%); mp 168–170 ◦ C. Rf : 0.33 (n-hexane/ethyl acetate; 1:2). IR (KBr, cm−1)vmax
2901, 1724 (C=O), 1614, 1512 (C=N), 1348, 1193, 752. 1 H NMR (400 MHz, DMSO-d6) δ 7.83–7.74 (m, 3H),
7.30–7.23 (m, 3H), 7.12–7.09 (m, 3H), 6.83–6.76 (m, 3H), 5.90 (d, J = 10.4 Hz, 2H, 2×CH), 5.53 (s, 4H),
5.53 (s, 4H, 2×CH2), 4.75 (d,J = 10.4 Hz, 2H, 2×CH), 3.98 (d,J = 6.0 Hz, 2H, Ph-CH2 -Ph), 2.98 (m, 12H,
2×NMe2). 13 C NMR (100 MHz, DMSO-d6) δ 175.4 (C=O), 172.2 (C=O), 170.8 (C=N), 168.3 (C=N), 152.8,
130.1, 129.9, 129.0, 128.9, 128.8, 127.4, 112.9, 112.5, 112.3, 83.9 (CH), 58.7 (CH), 44.8 (CH2). LC-MS (80 eV)
(m/z, %) = 819 (M+ -N2 , 34), 719 (17), 693 (100), 433 (74), 410 (87). HRMS (TOF MS ES+): Measured;
847.3181; Calculated for C43 H39 N14 O6 , 847.3177.
4. Conclusions
A simple and practical method for the preparation of 11 novel phenylsulfonyl substituted triazoles carrying a
3-p-substituted phenyl-1,2,4-oxadiazole unit and 10 novel bis dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(3aH,5H )-
diones carrying a 3-para-substituted phenyl-1,2,4-oxadiazole unit is introduced. The target compounds were
assayed against MCF-7 breast cancer cells, but IC50 values were not low. It was found that especially when R
= H, Me, MeO, I, NO2 , F, and Cl in both series compounds show somewhat higher cytotoxicity against these
cells.
Acknowledgments
˙
Abant Izzet Baysal University, Directorate of Research Projects Commission (BAP grant no. 2010.03.03.336),
¨
and the Scientific and Technological Research Council of Turkey (TUBITAK, grant no. 109T621) are gratefully
˙
acknowledged for their financial support.
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