Synthesis, Characterization and Thermal Behavior Study of New 1,2,3-Triazole Derivatives Containing 1,3,4-Oxadiazole Ring

Introduction

The knowledge of chemistry of heterocyclic compounds represents a basic point for the development of new heterocycles compounds that have an important role in agrochemical, pharmaceuticals and materials science.^1–3 Interestingly, azole structures being the most common among different classes of heterocyclic compounds.⁴ Structurally, azoles are composed of five-membered rings containing nitrogen atom and at least one other non-carbon atom of either nitrogen, oxygen or sulphur as heteroatoms as shown in Figure 1.^5,6

Figure 1: Different structures of azole. Click here to view figure

 

Currently, 1,2,3-triazole and 1,3,4-oxadiazole derivatives have a special attention due to their remarkable biological, chemical and physical properties.^7–9 In general, 1,2,3-triazole ring system is one of two aromatic isomeric structures of the general formula C₂N₂OH₂.¹⁰ Currently, click reaction is a method choice for the synthesis of 1,2,3-triazole ring.^11–13 This click reaction is described as a copper (I) catalyzed azide-alkyne 1,3-dipolarcycloaddition (CuAAC) and a simple synthetic route in relatively high yields with high regioselectivity to produce 1,4-disubstituted-1,2,3-triazole derivatives.^14–16 While, 1,3,4-oxadiazole ring system can be described as one of four isomers that have the molecular formula C₂N₂OH₂.^17,18 Depending on the starting materials that are used, several synthetic routes have been followed in the literatures for the synthesis of 1,3,4-oxadiadole derivatives.^19,20 However, the common synthetic approach is a cyclization reaction of the intermediate acylsemicarbazides in the presence of a variety of dehydrating agents such as thionyl chloride and polyphosphoric acid to introduce 2-amino-1,3,4-oxadiazole derivatives.^21,22 As the combination of two or more pharmacophores in one molecule is a strategy for development of new compounds, we are interested in synthesizing a new heterocyclic compounds containing 1,2,3-triazole and 1,3,4-oxadiazole rings combined in one molecule.

Experimental

Chemicals and Instruments

All solvents and starting materials were purchased from commercially available sources and they were directly used without further purification. FT-IR spectra were recorded on an FT-IR–8400S plus spectrometer operating from 4000–500 cm^-1 as KBr disc. ¹H-NMR spectra were recorded at 500 MHz on a Bruker AC 400 spectrometer. Mass data were measured on Agilent Technology (HP). TG-DTG analysis was performed by using a Perkin Elmer TG 4000 at the temperature ranged 39-900°C, with flow rate 20 ml/min and heating rate 40°C/min under nitrogen current.

Procedures

Synthesis of substituted phenyl azides (1-5)

All phenyl azides that were used in the present work were synthesized according to the modified procedure that was described in the literature.²³

General procedure for the synthesis of 1,2,3-triazole derivatives (6-10)

To a stirred aqueous solution containing CuSO₄.5H₂O (0.25 g, 1.03 mmol) and sodium ascorbate (0.38 g, 1.93 mmol), a mixture of tert-butanol: water (30.0 ml 2:1) was added. To the resulted solution, propiolic acid (1.2 ml, 20.0 mmol) and a substituted-phenyl azide (20.0 mmol) were added, sequentially. The reaction mixture was then stirred at 50°C for overnight. The reaction mixture was then allowed to cool into room temperature before addition of water (100 ml). The formed precipitate was then collected by filtration under vacuum, washed with ether and dried to give the titled compounds as solid products.

Synthesis of 1-(3-methoxyphenyl)-1H-1,2,3-triazolyl-4-carboxylic acid (6)

It was prepared by using 1-azido-3-methoxy-benzene 1 (2.98 g, 20.0 mmol): Yield (3.3 g, 77%) as a gray solid. FT-IR (KBr disc, cm^-1), 3576-2400 (OH, COOH), 3136 (Ar-H), 2947 (C-H, aliphatic), 1706 (C=O), 1647 (C=C-triazole), 1612 (Ar, C=C) and 1422 (-N=N-). ¹H-NMR (500 MHz, DMSO-d₆): δ= 3.4 (s, 3H, OCH₃), 7.49-7.57 (m, 4H, Ar-H) and 9.4 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₀H₉N₃O₃= 219.06, found= 219.1.

Synthesis of 1-(3-methylphenyl)-1H-1,2,3-triazolyl-4-carboxylic acid (7)

It was prepared by using 1-azido-3-methyl-benzene 2 (2.66 g, 20.0 mmol): Yield (2.03 g, 50%) as a gray solid. FT-IR (KBr disc, cm^-1), 3525-2400 (OH, COOH), 3063 (Ar-H), 2922 (C-H aliphatic), 1708 (C=O), 1654 (C=C-triazole), 1619 (Ar, C=C) and 1383 (-N=N-). ¹H-NMR (500 MHz, DMSO-d₆): δ= 2.1 (s, 3H, CH₃), 6.6-7.8(m, 4H, Ar-H) and 8.89 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₀H₉N₃O₂= 203.07, found= 203.1.

Synthesis of 1-(3-nitrophenyl)-1H-1,2,3-triazolyl-4-carboxylic acid (8)

It was prepared by using 1-azido-3-nitro-benzene 3 (3.8 g, 20.0 mmol): Yield (3.9 g, 84%) as light green solid. FT-IR (KBr disc, cm^-1), 3500-2500 (OH, COOH), 3113 (Ar-H), 1695 (C=O, COOH), 1631 (C=C-triazole), 1594 (Ar, C=C), 1390 (-N=N-) and 1315, 1257 (asymmetric, symmetric NO₂). ¹H-NMR (500 MHz, DMSO-d₆): δ= 13.3 (s, 1H, COOH), 7.9-8.9 (m, 4H, Ar-H) and 9.05 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₉H₆N₄O₄= 234.04, found= 234.01.

Synthesis of 1-(2-nitrophenyl)-1H-1,2,3-triazolyl-4-carboxylic acid (9)

It was prepared by using 1-azido-2-nitro-benzene 4 (3.8 g, 20.0 mmol): Yield (3.4 g, 70%) as a gray solid. FT-IR (KBr disc, cm^-1), 3500-2700 (OH, COOH), 3115 (Ar-H), 1720 (C=O), 1608 (C=C-triazole), 1589 (Ar, C=C), 1404 (-N=N-), 1356 and 1313 (asymmetric, symmetric NO₂). ¹H-NMR (500 MHz, DMSO-d₆): δ= 7.3-8.4(m, 4H, Ar-H) and 8.7 (s, ¹H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₉H₆N₄O₄= 234.04, found= 234.0.

Synthesis of 1-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid (10)

It was prepared by using 1-azido-4-bromo-benzene 5 (3.96 g, 20.0 mmol): Yield (4.7 g, 88%) as a white solid. FT-IR (KBr disc, cm^-1), 3500-2400 (OH, COOH), 3128 (Ar-H), 1705 (C=O), 1656 (C=C-triazole), 1591 (Ar, C=C), 1413 (-N=N-) and 825 (C-Br). ¹H-NMR (500 MHz, DMSO-d₆): δ= 13.2 (s, 1H, COOH), 7.6-8.8(m, 4H, Ar-H) and 9.1 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₉H₆BrN₃O_{2 =} 266.96, found= 266.07.

General procedure for synthesis of 1,3,4-oxadiazoles derivatives (11-15)

An appropriate 1,2,3-triazole derivative (6-10) (10.0 mmol) and semicarbazide hydrochloride (1.11 g, 10.0 mmol) were dissolved in POCl₃ (25 ml). The resulting reaction mixture was refluxed for overnight. The reaction mixture was then allowed to cool into room temperature before being slowly poured onto crush-ice (200 g). The formed precipitate was stirred in the same solution for 15 minutes before being treated carefully with an aqueous solution of sodium hydroxide 50%. The precipitate was then collected by filtration under vacuum, washed with water and dried.

Synthesis of 2-amino-5-[1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (11)

It was prepared by using compound 6 (2.19 g, 10.0 mmol): Yield (2.1 g, 85%) as a light green solid. FT-IR (KBr disc, cm^-1), 3136 (Ar-H), 1653 (C=N), 1610 (C=C-triazole), 1595 (Ar, C=C) and 1440 (N=N). ¹H-NMR (500 MHz, DMSO-d₆): δ= 3.7 (s, 3H, OCH₃), 4.3 (s, 2H, NH₂), 7.0-7.9 (m, 4H, Ar-H) and 8.8 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₉H₇N₃O₃= 258.09, found= 258.01.

Synthesis of 2-amino-5-[1-(3-methylphenyl)-1H-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (12)

It was prepared by using compound 7 (2.03 g, 10.0 mmol): Yield (2.17 g, 90%) as a dark green solid. FT-IR (KBr disc, cm^-1), 3059 (Ar-H), 1626 (C=N), 1595 (C=C-triazole), 1558 (Ar, C=C) and 1363 (-N=N-). ¹H-NMR (500 MHz, DMSO-d₆): δ= 2.0 (s, 3H, CH₃), 7.3-7.9 (m, 4H, Ar-H) and 8.7 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₁H₁₀N₆O= 242.09, found= 242.01.

Synthesis of 2-amino-5-[1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (13)

It was prepared by using compound 8 (2.34 g, 10.0 mmol): Yield (2.0 g, 74%) as a green solid. FT-IR (KBr disc, cm^-1), 3113 (Ar-H), 1664 (C=N), 1632 (C=C-triazole), 1593 (Ar, C=C) and 1352 (-N=N). ¹H-NMR (500 MHz, DMSO-d₆): δ= 4.36 (s, 2H, NH₂), 7.4-8.02 (m, 4H, Ar-H) and 8.8 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₀H₇N₇O₃= 273.06, found= 273.0.

Synthesis of 2-amino-5-[1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl]-1,3,4-oxadiazole (14)

It was prepared using compound 9 (2.34 g, 10.0 mmol): Yield (1.99 g, 73%) as a brown solid. FT-IR (KBr disc, cm^-1), 3119 (Ar-H), 1653 (C=N), 1608(C=C-triazole), 1590 (Ar, C=C) and 1348 (-N=N-). ¹H-NMR (500 MHz, DMSO-d₆): δ= 4.9 (s, 2H, NH₂), 7.3-8.2 (m, 4H, Ar-H) and 8.72 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₀H₇N₇O₃ = 273.06, found= 273.1.

Synthesis of 2-amino-5-[1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl]-1,3,4-oxadiazole  (15)

It was prepared by using compound 10  (2.68 g, 10.0 mmol): Yield (2.42 g, 79%), as a green solid. FT-IR (KBr disc, cm^-1), 3126 (Ar-H), 1654 (C=N), 1595 (C=C-triazole), 1560 (Ar, C=C) and 1435 (-N=N-). ¹H-NMR (500 MHz, DMSO-d₆): δ= 4.37 (s, 2H, NH₂), 7.4-7.99 (m, 4H, Ar-H) and 8.86 (s, 1H, C=CH-triazolyl). HPMS-EI⁺ (m/z): calc. for C₁₀H₇BrN₆O= 307.98, found= 308.1.

Results and Discussion

Chemistry

For the synthesis of the target 1,3,4-triazole derivatives 6-10, a series of electron-rich and poor p-, o– and m-substituted phenyl azido compounds 1-5 was designed as azido components for CuAAC reaction. These intermediates were synthesized via reaction of diazonium salts with sodium azide (Scheme 1) according to the procedure that was described in the literature.²³ Choosing of these different azides is to investigate the effect of the nature and position of the substituent group on the reactivity of their corresponding azides towards click reaction and on the thermal stability of the synthesized compounds 6-15. Thus, following our previous investigations, the synthetic route involved addition of propiolic acid and an appropriate azide 1-5 to a solution of tert-butanol: water (2:1) containing CuSO4.5H₂O and sodium ascorbate as described in Scheme 1.

Scheme 1: Synthesis of 1,2,3-triazole derivatives. Click here to view scheme

 

Sodium ascorbate was used as a reducing agent to produce in situ Cu (I) that is required to perform a copper (I) catalyzed azide-alkyne cycloaddition reaction and this reaction is proceeded according to the general suggested mechanism that is describe in scheme 2.

Scheme 2: A general mechanism for the synthesis of 1,2,3-triazole derivatives.24 Click here to view scheme

 

The reaction mixture was heated up to 50°C and left to stir for overnight. By the first attempt, all synthesized m-, p- and o-substituted phenyl azides displayed a reactivity towards click reaction to give the titled compounds 6-10 in a relatively high yield. Our synthetic pathway highlighted a simple work up and the target products 6-10 were separated as precipitates from the reaction mixture as pure compounds with no need to purification by column chromatography. All newly synthesized compounds were characterized by FT-IR, ¹H-NMR and Mass spectra.

As the synthesized 1,2,3-triazole derivatives 6-10 containing a carboxyl function group, so it can be used to extend their structure. In the current work, it was aimed to combine the synthesized 1,2,3-triazole ring system with 1,3,4-oxadiazole ring system in one molecule to obtain new heterocyclic compounds such as 11-15 as described in Scheme 3. To achieve this aim, the synthesized 1,2,3-triazole derivatives 6-10 and semicarbazide hydrochloride were condensed in the presence of POCl₃. The latter is chlorinating reagent for carboxyl function, which either used as such or in combination with a solvent.

Scheme 3: Synthesis of 1,3,4-oxadiazole derivatives. Click here to view scheme

 

The synthetic route that was devised for the synthesis of the target compounds 11-15 followed the procedures that were described in the litertures.^25,26 The key step in this synthetic route is formation in situ the intermediate acylsemicarbazides, followed by a dehydro-cyclization reaction according to a general mechanism that is shown in Scheme 4. In general, this reaction was preceded smoothly without a problem seen to obtain the target compounds 11-15 in a simple work up and pure enough. The structure of the synthesized compounds 6-15 were characterized by FT-IR, ¹H-NMR and Mass spectra.

Scheme 4: A general mechanism for the synthesis of 1,3,4-oxadiazoles derivatives.27,28 Click here to view scheme

 

Thermal Behavior Study

Thermal analysis is an important technique used to investigate the thermal behavior of compounds such as a presence of intermediates, degradation process, melting and final known composition.^29–31 In the current study, the thermal analysis of the target compounds 6-15 was achieved by using TGA combine DTG techniques. Thermogravimetry (TG) is a useful analytical technique used for thermal analysis that is used for recording weight losing of a tested sample as a function of temperature.³² While, DTG curves help to permit the direct application of the rate function of the change in the weight of the target sample to the study of phenomena occurring during thermogravimetric analysis. Where, the area of the peak (T_initial, T_final) is directly proportional to the mass loss over the same temperature range and the DTG peak high at any temperature gives the rate of mass loss (dm/dT in mg/min unit).³³ Practically, depending on the nature of the m-, p-, o-rich or poor-electron substituted phenyl that is attached to N1-position of 1,2,3-triazole ring, TG-DTG curves of compounds 6-10 are depicted in Figures 2 and 3. It is evident from these figures and Table 1 that compounds 6,7,8,9 and 10 are thermally stable up to 205, 223, 182, 135 and 222°C, respectively, followed a single decomposition stage. In addition, as expected compounds 8 and 9 displayed a less thermal stability due to their structures contain nitro group which can be described as thermally unstable group. Since, 1,3,4-oxadiazole ring system is considered a thermally stable species, TG-DTG measurements indicated that the synthesized compounds 11-15 have a higher thermal stability than their precursors 6-10 up to 205°C then decomposed in a single stage as shown in Figures 4 and 5 and Table 1.

Table 1: TG-DTG data of compounds 6-15.

Comp. No	TG decomposition temperature Range (°C)	Losing weight (%)	DTGmix (°C)
6	205-302	49	258
7	223-243	51	234
8	182-232	42	220
9	135-195	97	188
10	222-283	29	235
11	250-378	30	342
12	206-403	23	326
13	248-363	31	327
14	215-382	24	285
15	238-402	38	343

 

Figure 2: TG curves of compounds 6-10. Click here to view figure

Figure 3: DTG curves of compounds 6-10. Click here to view figure

Figure 4: TG curves of compounds 11-15. Click here to view figure

Figure 5: DTG curves of compounds 11-15. Click here to view figure

 

Conclusions

In conclusion, a series of electron-rich and poor phenyl azide compounds displayed a reactivity to react with propiolic acid via click reaction (CuAAC). Since the synthesised 1,2,3-triazole derivatives containing a carboxyl functional group, it used to extend their structure with 2-amino-1,3,4-oxadiazole ring system via reaction with semicarbazide hydrochloride in the presence of POCl₃. Furthermore, all synthesized heterocyclic compounds displayed a relatively good thermal stability.

Acknowledgments

The authors would like to thank the department of chemistry/College of Science/Al-Muthanna University for the facilities during doing this work.

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