Novel sydnone derivatives carrying azidomethyl-1,2, 4-oxadiazole unit and their 1,3-dipolar cycloadditions

Article abstract of DOI:10.1080/00397911.2017.1279630

A series of 1,2,4-oxadiazolymethyl sydnones carrying azido group were synthesized and subjected to react with a variety of alkenic and acetylenic dipolarophilic reagents; N-phenyl maleimide, phenyl vinyl sulfone, and phenyl propiolic acid. All the new products are identified by spectral/physical data including high-resolution mass measurements and X-ray diffraction data.

Full text of DOI:10.1080/00397911.2017.1279630

Novel Sydnone Derivatives Carrying Azidomethyl-1,2,4-oxadiazole Unit and their
1,3-dipolar Cycloadditions
Yaşar Dürüst1,, Elif Yıldız1, Hamza Karakuş1, Benson M. Kariuki2
1Department of Chemistry, Abant İzzet Baysal University, Turkey
2School of Chemistry, Cardiff University, Cardiff, UK
Corresponding author Yaşar Dürüst . Email: yasardurust@ibu.edu.tr
Abstract
A series of 1,2,4-oxadiazolymethyl sydnones carrying azido group were synthesized and
subjected to react with a variety of alkenic and acetylenic dipolarophilic reagents; N-
phenyl maleimide, phenyl vinyl sulfone and phenyl propiolic acid. All the new products
are identified by means of spectral/physical data including high resolution mass
measurements and X-ray diffraction data.
Graphical Abstract
KEYWORDS: sydnone; oxadiazole; triazole; azide; 1,3-dipolar cycloaddition
INTRODUCTION
1

Sydnones are among the important class of mesoionic systems which were discovered by
Earl and Mackney[1] and they have been receiving an increasing interest over the decades
due to their capability to be converted into heterocycles with potent biological
activities.[2–4] The electrophilic substitution of sydnones in C4 position is a well known
method for the preparation of a wide range of 4-heterocycle-substituted sydnones.[5,6]
1,2,4-Oxadiazole derivatives are also important skeletons of biologically or
pharmacologically important compounds. For example, muscarinic agonists, histamine
H3 antagonists, antitumoral, antiinflammatory and antimycobacterium tuberculosis
agents containing a 1,2,4-oxadiazole ring are among them.[7–12] On the other hand,
triazole rings have also attracted remarkable attention due to their biological activities
such as antifungal, anticonvulsant agents and especially popular in designing anticancer
agents.[13–17]
1,3-Dipolar cycloaddition route is a valuable process in order to assemble molecules
having fragments in biologically active agents of 5-membered nitrogen heterocycles.
From a synthetic standpoint, it may be considered worthy and in principle, available by a
sequence involving sydnone functionalization with azido group followed by
cycloaddition.
Taking account of above considerations together with our continuing interest in the 1,3-
dipolar cycloaddition chemistry of various ylides leading to triazoles and
spiropyrroles,[18-21] we focus herein on the synthesis of oxadiazolyl-substituted sydnones
2

starting from sydnones and their carboxamidoxime derivatives which were subsequently
converted into azidomethyl compounds. The latter were engaged in a series of
representative electron-deficient alkenes and alkynes: and their cycloaddition reactions.
These series of sydnones were reacted with three representative dipolarophiles: N-phenyl
maleimide, phenyl vinyl sulfone, and phenyl propiolic acid.
RESULTS AND DISCUSSION
N-Aryl sydnones 5a-f have been synthesized starting from 4-substituted anilines 1
through cyclodehydration of corresponding N-nitroso α-amino carboxylic acids 4
according to the previously reported procedures (Scheme 1).[22,23] In this way, we have
prepared 6 sydnone derivatives.
In order to convert sydnones 5 into 4-carboxamidoxime derivatives 9, a reaction
sequence has been utilized, which, first, transformed starting materials to sydnone
aldehydes 6 by means of Vilsmeer-Haack formylation.[24] Aldehydes 6 were then
transformed into aldoximes 7 which were dehydrated to give nitriles 8.[25] Sydnone
nitriles 8 have been reacted with hydroxylamine to yield sydnone amidoximes 9 (Scheme
2). In this way, we have prepared 3 sydnone carboxamide oximes.
Sydnone-4-carboxamidoximes 9 have been converted into 5-chloromethyl-3-
substitutedphenyl-1,2,4-oxadiazoles 10a-c[26] by their reaction with chloroacetyl chloride
in benzene under reflux. Sydnone azides 11a-d were obtanied from the reaction of
oxadiazoles 10a-d with NaN3 according to previously reported prodecure (Scheme 3).[21]
3

Among the important spectral characteristics of these novel compounds are azide and
carbonyl streching absorptions in the IR spectra at around 2100 and 1750 cm-1; CH2
protons and carbon at around 4.50 and 45 ppm, respectively, in the NMR spectra.
One of the chloromethyl oxadiazolyl sydnones; 10c has been elucidated by obtaining X-
Ray ORTEP view (Figure 1).
Sydnone azides 11a-c were then subjected to 1,3-dipolar cycloaddition with N-phenyl
maleimide 12 to give cycloadducts 13a-c which were absolutely identified by means of
X-ray diffraction data (Scheme 4, Figure 2).
Upon examination of the IR data, strong absorptions arising from both sydnone and
maleimide portions of the cycloadducts at around 1770 -1720 cm-1 were observed. 1H
NMR spectra also showed the methylene protons as separate doublets at around 5.55 and
5.20 ppm while the bridge protons resonated as doublets at 5.65 and 4.55 ppm. Carbonyl
carbons appeared at 175-165 ppm region, bridge carbons at around 83 and 56 ppm and
methylene carbons at 44 ppm, respectively. These results are in accord with the previous
findings.[21 ]We were also able to obtain an X-ray ORTEP diagram of 13b (Figure 2).
Azido sydnones 11a and 11b were also assayed for 1,3-dipolar cycloaddition with
electron deficient alkene, phenyl vinyl sulfone 14 and cycloadducts 15a,b were obtained
in lower yields 13% and 10% respectively (Scheme 5).
4

Spectral characteristics of these cycloadducts included a carbonyl absorption in the IR
spectrum emerged from the sydnone fragment, symmetric and asymmetric stretching
vibrations of sulfone moiety at 1325-1140 cm-1. The proton NMR signals of the triazoline
ring and methylene hydrogens existing in the region of 5.60-3.50 ppm were indicative.
All these resonances coincide with the previous reports regarding the associated
compounds.[27,28] We have utilized a number of different reaction conditions for other
azido sydnones (11c,d) to obtain a variety of cycloadducts carrying phenyl sulfonyl
group, but all the attempts failed, that is, no triazole products could form.
In order to explore the cycloaddition of novel azides with an alkyne dipolarophile; we
used phenyl propiolic acid 16 and it smoothly underwent cycloaddition to afford the
cycloadducts 17a-d with the azido sydnones 11a-d (Scheme 6).
1,3-Dipolar cycloadditon of azido sydnones 11a-d with phenyl propiolic acid resulted in
regioselective formation of the 4-phenyl regioisomers (triazoline ring numbering) but not
5-phenyl regioisomers which is supported by the X-ray diffraction data of 17b (Figure 3),
as well as by an earlier report utilizing electron-deficient alkyne esters.[25] Indicative
spectral characteristics are the carbonyl absorptions of sydnone part, and C=N
absorptions in the IR spectra. 1H NMR spectra of products showed a triazole proton at
around 7.90 ppm and metyhylene protons at around 5.90 ppm.
We also attempted to carry out a second cycloaddition with the sydnone fragment of the
cycloadducts but despite numerous trials no reaction occurred; much likely to be
5

attributed to the sterical bulkiness around the ylide that prevents from the approach of
dipolarophiles.
One of our goals associated with this work, was to screen the novel products for their
bioactivities, but, due to low amounts of the end products, it was not possible at this
moment. However, we have made some predictions by means of Lipinski’s rule of five
(RO5), a rule of thumb to evaluate druglikeness or determine if a chemical compound
with a certain pharmacological or biological activity has properties that would make it a
likely orally active drug in humans.[29-31] Below is given a table indicating the estimated
Lipinski values (Table 1). In this regard, higher scores are related to the methoxy and
methyl subtituted adducts.
CONCLUSION
Through this work we have demonstrated a ten-step reaction sequence leading to the
synthesis of the novel sydnones bearing azidomethyl-1,2,4-oxadiazole fragment and their
1,3-dipolar cycloaddition reaction with a series of electron deficient dipolarophilic
reagents; N-phenyl maleimide, phenyl vinyl sulfone and phenyl propiolic acid. The
compounds 13, 15 and 17 resulted from 1,3-dipolar cycloaddition of the sydnone azides
preferrentially by azide-dipolarophile reaction, but no further reactivity has been
observed between sydnone-azide cycloadducts and dipolarophiles even if too many
reaction conditions were assayed.
EXPERIMENTAL
6

Melting points were determined on a Meltemp apparatus and are uncorrected. Infrared
spectra were obtained from KBr pellets or neat on NaCl plates for liquids and were
recorded on a SHIMADZU FTIR-8400S spectrophotometer. NMR spectra were recorded
on Jeol and Varian spectrometers operating at 400 MHz for 1H and at 100 MHz for 13C,
all at 25 ºC, as specified for each data set. LC-MS spectra were obtained from Waters
2695 Alliance Micromass ZQ instrument. High Resolution Mass Spectra have been
obtained from Waters Lct Premier XE oa-TOF Mass Spectrometer (Waters Corporation,
Milferd, MA, USA). Single crystal X-ray diffraction data were obtained by Bruker Smart
Apex II Quazar and Nonius Kappa CCD instruments. All chemical shifts are reported in
ppm relative to TMS. Coupling constants (J) are reported in Hz. Routine TLC analyses
were carried out on pre-coated silica gel plates with fluorescent indicator. Flash column
chromatography was performed on silica gel (230-400 Mesh ASTM). A rotary TLC
apparatus (Chromatotron) was utilized for further separation and purifications. Stain
solutions of potassium permanganate and iodine were used for visualization of the TLC
spots.
Typical Reaction Procedure For The Synthesis Of 4-(5-(Chloromethyl)-1,2,4-
Oxadiazol-3-Yl)-3-(4-Methylphenyl)Sydnone (10a)[22]
A solution of chloroacetylchloride (0.070 g, 0.62 mmol) in benzene (2 mL) was added
dropwise to a solution of 3-(4-methoxyphenyl)sydnone-4-carboxamidoxime 9a (0.360 g,
1.54 mmol) in benzene (20 mL) and the mixture was heated under reflux for 24h. The
progress of the reaction was monitored by TLC. The reaction mixture was concentrated
7

in vacuo, and the crude residue was purified by flash column chromatography (n-
hexane:ethyl acetate; 4:1) to give 10a as a white solid.
4-(5-(Chloromethyl)-1,2,4-Oxadiazol-3-Yl)-3-(4-Methylphenyl)Sydnone (10a)
Yield: 0.400 g, 89%. Mp. 155-156oC. Rf: 0.59 (n-hexane:ethyl acetate; 1:1). IR (KBr,
v:cm-1): 3014, 2960, 1797, 1778 (sydnone C=O), 1568 (C=N), 1510, 1444, 1282, 1199,
1058, 1010, 954, 891, 779, 750 (C-Cl). 1H NMR (400 MHz, CDCl3): H= 7.45 (d, J=8.4
Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 4.66 (s, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3):
C= 174.5 (sydnone C=O), 158.5 (C=N), 143.6, 130.3, 124.7, 32.9 (CH2), 21.6 (CH3).
LC-MS (80 eV) (m/z) (%): 356 ([M+CH3CN+Na]+, 100), 293 ([M+H]+, 48), 248 (21).
HRMS: m/z (ESI-TOF, [M+H]+) calcd for C12H10N4O3Cl: 293.0441; found: 293.0428.
Typical Reaction Procedure For The Synthesis Of 4-(5-(Azidomethyl)-1,2,4-Oxadiazol-
3-Yl)-3-(4-Methylphenyl)Sydnone (11a)[19,23]
To a stirred solution of 4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-3-(4-
methylphenyl)sydnone 10a (0.400 g, 1.37 mmol) in a 10 mL water/acetone mixture (1:4)
was added sodium azide (0.098 g, 1.51 mmol). The resulting suspension was stirred at
room temperature for 24h. Dichloromethane (DCM) was added to the mixture and the
organic layer was separated. The aqueous layer was extracted with 3x10 mL aliquots of
DCM and the combined organic layers were dried over sodium sulfate. Solvent was
removed under reduced pressure to give 11a as a light yellow solid.
4-(5-(Azidomethyl)-1,2,4-Oxadiazol-3-Yl)-3-(4-Methylphenyl)Sydnone (11a)
8

Yield: 0.200 g, 49%. Mp. 98-101oC. Rf: 0.58 (n-hexane:ethyl acetate; 1:1). IR (KBr,
v:cm-1): 3061, 2991, 2922, 2098 (N=N=N), 1759, 1743 (C=O), 1558 (C=N), 1508, 1435,
1319, 1273, 1197, 1056, 1016, 960, 817, 740. 1H NMR (400 MHz, CDCl3): H= 7.44 (d,
J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 4.51 (s, 2H), 2.49 (s, 3H).13C NMR (100 MHz,
CDCl3): C= 174.2 (sydnone C=O), 164.8 (C=N), 158.4 (C=N), 143.4, 131.8, 130.3,
124.5, 44.6 (CH2), 21.5 (CH3). LC-MS (80 eV) (m/z) (%): 363 ([M+CH3CN+Na]+, 94),
300 ([M+H]+, 100). HRMS: m/z (ESI-TOF, [M+H]+) calcd for C12H10N7O3: 300.0845;
found: 300.0834.
Typical Reaction Procedure For The Synthesis Of 4-(5-(((3as,6ar)-4,6-Dioxo-5-
Phenyl-4,5,6,6a-Tetrahydropyrrolo[3,4-D][1,2,3]Triazol-1(3ah)-Yl)Methyl)-1,2,4-
Oxadiazol-3-Yl)-3-(4-Methylphenyl)Sydnone (13a)
A mixture of N-phenyl maleimide 12 (0.030 g, 0.175 mmol) and 4-(5-(azidomethyl)-
1,2,4-oxadiazol-3-yl)-3-(4-methylphenyl)sydnone 11a (0.050 g, 0.167 mmol) were stirred
in benzene (17 mL) and the mixture was heated under reflux for 2-4 d. 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; 1:2) to
give 13a as a light yellow solid.
4-(5-(((3as,6ar)-4,6-Dioxo-5-Phenyl-4,5,6,6a-Tetrahydropyrrolo[3,4-D][1,2,3]Triazol-
1(3ah)-Yl)Methyl)-1,2,4-Oxadiazol-3-Yl)-3-(4-Methylphenyl)Sydnone (13a)
Yield: 0.020 g, 25%. Mp. 143-144oC. Rf: 0.19 (n-hexane:ethyl acetate; 1:1). IR (KBr,
v:cm-1): 1766 (sydnone C=O), 1720 (C=O), 1564 (C=N), 1492, 1379, 1195, 1041, 817,
9

742. 1H NMR (400 MHz, CDCl3): H= 7.48-7.38 (m, 4H), 7.35 (d, J=2.8 Hz, 2H), 7.2 (t,
J=2.0 Hz, 1H), 7.19 (t, J=1.6 Hz, 1H), 5.62 (d, J=10.8 Hz, 1H), 5.48 (d, J=18.0 Hz, 1H),
5.22 (d, J=18.0 Hz, 1H), 4.56 (d, J=10.8 Hz, 1H), 2.51 (s, 3H). 13C NMR (100 MHz,
CDCl3): C= 174.3 (sydnone C=O), 170.9 (C=O), 168.3 (C=O), 164.8 (C=N), 158.1
(C=N), 143.7 (C-CH3), 131.7, 130.4, 129.5, 129.3, 126.8, 126.3, 126.0, 124.6, 83.2 (CH),
57.0 (CH), 44.3 (CH2), 21.5 (CH3). HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C22H17N8O5: 473.1322; found: 473.1325.
Typical Reaction Procedure For The Synthesis Of 3-(4-Methylphenyl)-4-(5-((5-
(Phenylsulfonyl)-4,5-Dihydro-1H-1,2,3-Triazol-1-Yl)Methyl)-1,2,4-Oxadiazol-3-
Yl)Sydnone (15a)
A mixture of phenyl vinyl sulfone 14 (0.024 g, 0.135 mmol) and 4-(5-(azidomethyl)-
1,2,4-oxadiazol-3-yl)-3-(4-methylphenyl)sydnone 11a (0.040 g, 0.134 mmol) were stirred
in toluene (7 mL) and the mixture was heated under reflux for 6d. The reaction was
monitored by TLC. The reaction mixture was concentrared in vacuo, and the crude
residue was purified by flash column chromatography (n-hexane:ethyl acetate; 1:2) to
give 15a as a light yellow solid.
3-(4-Methylphenyl)-4-(5-((5-(Phenylsulfonyl)-4,5-Dihydro-1H-1,2,3-Triazol-1-
Yl)Methyl)-1,2,4-Oxadiazol-3-Yl)Sydnone (15a)
Yield: 8mg, 13%. Mp. 84-86oC. Rf : 0.20 (n-hexane:ethyl acetate; 1:1). IR (KBr, v:cm-1):
2958, 2927, 2852, 1770 (sydnone C=O), 1564 (C=N), 1446, 1321 (asym SO2), 1240,
1151 (sym SO2), 1082, 1056, 935, 821, 744. 1H NMR (400 MHz, CDCl3): H= 7.95 (dd,
10

J=8.0, 0.4 Hz, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.60 (t, J=8.0 Hz, 2H), 7.42 (dd, J=11.6, 8.8
Hz, 4H), 5.56 (dd, J=8.4, 7.2 Hz, 1H), 5.19 (d, J=17.6 Hz, 1H), 4.96 (d, J=17.2 Hz, 1H),
3.85 (dd, J=11.6, 7.6 Hz, 1H), 3.52 (t, J=12.0 Hz, 1H), 2.47 (s, 3H). 13C NMR (100 MHz,
CDCl3): C= 173.5 (sydnone C=O), 164.7 (C=N), 158.2 (C=N), 143.6 (C-CH3), 136.0,
134.8, 131.7, 130.3, 129.5, 129.3, 124.7, 95.1 (C-SO2), 44.9 (CH2), 44.2 (CH2), 21.5
(CH3). LC-MS (80 eV) (m/z) (%): 490 ([M+Na]+, 100), 468 ([M+H]+, 19), 459 (60). ESI-
MS (80 eV) (m/z) (%): 466 ([M-H], 100). HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C20H18N7O5S: 468.1090; found: 468.1081.
Typical Reaction Procedure For The Synthesis Of 3-(4-Methylphenyl)-4-(5-((5-Phenyl-
1H-1,2,3-Triazol-1-Yl)Methyl)-1,2,4-Oxadiazol-3-Yl)Sydnone (17a)
Method A
A mixture of phenylpropiolic acid 16 (0.026 g, 0.175 mmol) and 4-(5-(azidomethyl)-
1,2,4-oxadiazol-3-yl)-3-(4-methylphenyl)sydnone 11a (0.050 g, 0.167 mmol) were stirred
in benzene (17 mL) and the mixture was heated under reflux for 4d. The reaction was
monitored by TLC. But, no reaction occurred.
Method B
A mixture of 4-(5-(azidomethyl)-1,2,4-oxadiazol-3-yl)-3-(4-methylphenyl)sydnone 11a
(0.050 g, 0.167 mmol), catalytic amount of CuSO4.5H2O (0.002 g, 0.008 mmol), Na-L-
ascorbate (0.009 g, 0.043 mmol) and phenylpropiolic acid 16 (0.026 g, 0.175 mmol) were
stirred in t-BuOH/water mixture (1 mL;2 mL, 1:2) at room temperature for 2d. Then, the
11

reaction mixture was extracted with ethyl acetate three times. The combined organic
layers were dried over sodium sulfate. The solvent was evaporated under reduced
pressure to give 17a as a brown solid.
3-(4-Methylphenyl)-4-(5-((5-Phenyl-1H-1,2,3-Triazol-1-Yl)Methyl)-1,2,4-Oxadiazol-3-
Yl)Sydnone (17a)
Yield: 0.060 g, 90%. Mp. 129-131oC. Rf: 0.21 (n-hexane:ethyl acetate; 1:1). IR (KBr,
v:cm-1): 3047, 2935, 1780 (sydnone C=O), 1625, 1568 (C=N), 1450, 1338, 1232, 1068,
908, 815, 761. 1H NMR (400 MHz, CDCl3): H= 7.88 (s, 1H), 7.80 (d, J=7.2 Hz, 2H),
7.44 (t, J=7.2 Hz, 2H), 7.40-7.34 (m, 3H), 7.29 (d, J=8.4 Hz, 2H), 5.85 (s, 2H), 2.34 (s,
3H). 13C NMR (100 MHz, CDCl3): C= 167.4 (sydnone C=O), 164.8 (C=N), 143.7,
131.5, 130.2, 129.7, 128.9, 128.6, 125.7, 124.6, 124.1, 120.2, 96.8, 45.0 (CH2), 21.4
(CH3). LC-MS (80 eV) (m/z) (%): 424 ([M+Na]+, 83), 402 ([M+H]+, 100), 282 (93). ESI-
MS (80 eV) (m/z) (%): 400 ([M-H]-, 100). HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C20H16N7O3: 402.1315; found: 402.1296.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra for synthesized compounds and X-ray
data for compounds 10c (CCDC No:1005653), 13b (CCDC No: 1024963) and 17b
(CCDC No: 1019441). This material can be found via the “Supplementary Content”
section of this article’s webpage.
ACKNOWLEDGMENTS
12

Abant İzzet Baysal University, Directorate of Research Projects Commission (BAP grant
no. 2012.03.03.557) is gratefully acknowledged for financial support. Authors thank Dr.
Yunus Zorlu (Gebze Technical University, Kocaeli, Turkey) for X-ray diffraction data.
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15

Table 1. Estimated Lipinski values for the 13,15,17.
R(Sydnone N3- cLogP
substitution)
Solubili MW
ty
TPSA
Drugliken Drugsc
Entry
ess
ore
C6H4-Me
C6H4-OMe
C6H4-Br
C6H4-Me
C6H4-OMe
C6H4-Me
C6H4-OMe
C6H4-Br
CH3
-3.13
-3.54
-2.75
-2.11
-2.52
-1.43
-1.84
-1.04
-3.16
-4.39
-4.06
-4.88
-4.28
-3.95
-4.36
-4.03
-4.85
-3.04
472.0
488.0
536.0
467.0
483.0
401.0
417.0
465.0
325.0
157.2
166.4
157.2
162.3
171.6
122.6
131.8
122.6
122.6
0.64
2.1
0.54
0.62
0.41
0.33
0.34
0.39
0.47
0.32
0.54
13a
13b
13c
15a
15b
17a
17b
17c
17d
0.09
-10.6
-9.09
-2.54
-1.05
-3.11
-1.25
16

Scheme 1. Synthesis of N-aryl sydnones 5a-f.
17

Scheme 2. Synthesis of sydnone-4-carboxamidoximes 9a-d.
18

Scheme 3. Synthesis of azido sydnones 11a-d.
19

Scheme 4. Cycloaddition of azido sydnones 11a-c with N-phenyl maleimide 12.
20

Scheme 5. Cycloaddition of azido sydnones 11a,b with phenyl vinyl sulfone 14.
21

Scheme 6. Cycloaddition of 11a-d with phenyl propiolic acid 16 affording 17a-d.
22

Figure 1. X-Ray ORTEP view of 10c.
23

Figure 2. X-Ray ORTEP view of 13b.
24

Figure 3. X-ray ORTEP view of 17b.
25