Synthesis and Characterization of Novel 2-Alkyl-1,3,4-Oxadiazoles Containing a Phenylazo Group

Abstract

An efficient method for the synthesis of novel phenylazo-containing moieties is described. The derivatives of 5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazole, substituted at position 2 of the heterocyclic scaffold with alkyl groups of different chain lengths, were prepared. The titled compounds were obtained using the appropriate 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines, which were directed to diazotization and subsequently coupled to phenol, resorcinol, and N,N-dimethylaniline. Additionally, we report a mild and effective procedure for the preparation of 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines via the selective reduction of the corresponding 2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles using sodium borohydride-tin(II) chloride dihydrate as the reducing system. The chemical structures of the prepared compounds were confirmed by ¹H- and ¹³C-NMR, IR, and UV-Vis spectroscopy.

1. Introduction

1,3,4-Oxadiazoles are a group of non-naturally occurring five-membered heterocyclic arrangements composed of two neighboring nitrogen atoms and one oxygen atom with carbon atoms. They have gained interest among researchers due to their broad spectrum of biological activity, such as anti-inflammatory, analgesic, anticancer, antibacterial, antifungal, antiviral, or blood-pressure-lowering interactions [1,2,3,4,5,6]. Except for medicine, 1,3,4-oxadiazoles have also been applied to agriculture in crop protection as pesticides fighting against weeds, insects, bacteria, and fungi [7,8,9]. Conjugated arrangements composed of such a core show interesting electron transfer or luminescent properties and can be used in the production of different types of conducting systems, including organic light-emitting diodes (OLEDs), laser dyes, scintillators, or optical brighteners [10,11,12,13]. These compounds have also been applied in materials science, where they act as anti-corrosion or blowing agents, or monomers for the production of heat-resistant polymers [14,15,16,17]. The extensive applicability of 1,3,4-oxadiazoles is the main reason for the exploration of efficient preparation methods. The most popular procedure employs N,N′-diacylhydrazines, which undergo cyclodehydration under the influence of sulfuric acid [18], thionyl chloride [19], polyphosphoric acid [20], phosphoryl chloride [21], trifluoromethanesulfonic anhydride [22], phosphorus pentoxide [23], or triphenylphosphine derivatives [24]. Another approach uses N-acylhydrazones in the synthesis of 1,3,4-oxadiazoles, where they undergo oxidative cyclization in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [25], cerium ammonium nitrate (CAN) [26], potassium permanganate (KMnO₄) [27], iron(III) chloride (FeCl₃) [28], tetravalent lead reagents [29], iodine (I₂/HgO), [30], bromine (Br₂/NaOAc) [31], chloramine T [32], and hypervalent iodine reagents [33]. Other methods for 1,3,4-oxadiazole formation include the reaction of acid hydrazides with carboxylic acids [34], aromatic aldehydes [26], or triethyl orthoesters [35], isomerization of 1,2,4-oxadiazoles [36], as well as the transformation of tetrazoles [37].

Azo dyes constitute the largest and most important class of synthetic dyes, in terms of production volume, consumption, and their possible applications [38,39,40,41]. They are characterized by the presence of one, two, or more chromophoric azo groups −N=N− connecting individual organic fragments, usually aromatic, into the dye molecule. Some such dyes, in addition to an azo group, contain other chromophores or functional groups that deepen the color (auxochromes, e.g., hydroxyl or amino groups and their substituted alkyl or aryl derivatives), modify the affinity to the different materials, and have solubility (e.g., carboxyl or sulfonic groups) [42]. The industrial process for the production of azo compounds is a two-step reaction sequence comprised of diazotization of primary aromatic amines and then coupling with an activated aromatic compound [43]. In general, the azo dyes are highly colorant and exhibit vivid colors, starting from yellows and oranges, through reds and violets, and ending even in blues or greens. A wide range of colors, strong coloring properties, affinity to various materials, and easy preparation promote their broad application in the dyestuff industry, food, cosmetics, photography, and pharmacy [43].

An interesting but relatively rarely investigated group of azo compounds are derivatives composed of 1,3,4-oxadiazole and azobenzene cores, which, in addition to intense color, exhibit other useful properties. 1,3,4-Oxadiazole-decorated azobenzenes have been used successfully in irradiation experiments to study their photoswitching potential (A, Figure 1) [44], while new highly fluorescent gelators based on 2-[(4-hydroxyphenyl)azophenyl]-1,3,4-oxadiazole (B, Figure 1) are promising precursors for the construction of photo-controllable luminescence molecular devices [45,46]. Reversibly switchable azomacrocycles derived from the symmetrically substituted 1,3,4-oxadiazole scaffold (C, Figure 1) were investigated by Zheng et al. [47]. In addition, Chen et al. synthesized a few groups of 2,5-disubstituted 1,3,4-oxadiazoles bearing azophenols and studied their anticancer activity (D, Figure 1) [48].

Here, we synthesized and examined another group of conjugated 1,3,4-oxadiazoles. The synthesis of novel azo compounds was studied, in particular 5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazole derivatives, substituted at position 2 of the heterocyclic scaffold with alkyl groups of a different chain length (G, Scheme 1). We obtained such compounds based on the classic diazotization reaction of 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines (F) and the subsequent coupling of the resulting diazonium salts with selected activated aromatics: phenol, resorcinol, and N,N-dimethylaniline (Scheme 1).

The corresponding conjugated nitro derivatives—2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles (E), obtained from acyclic reagents, served as precursors for the synthesis of 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines (F) in the preceding reduction reaction.

2. Results and Discussion

The new azo dyes containing 2-alkyl-1,3,4-oxadiazole scaffolds were prepared using derivatives of selected aliphatic and aromatic carboxylic acids, including hydrazides (3a–d) and acid chlorides (4d–f, Scheme 2). Acid hydrazides (3a–d) were generated via a two-step reaction sequence involving the esterification of carboxylic acids (1) with methanol in the presence of catalytic amounts of sulfuric acid, and subsequent substitution in the ester molecule (2) in the presence of hydrazine hydrate. Acid chlorides, including propanoyl chloride (4e) and 4-aminobenzoyl chloride (4f), were obtained by treating the appropriate carboxylic acid with thionyl chloride (SOCl₂). 4-Nitrobenzoyl chloride (4d) was synthesized from 4-nitrobenzoic acid, where phosphorus pentachloride (PCl₅) was used as the chlorinating agent (Scheme 2).

Then, hydrazides (3a–d) and acid chlorides (4e–d) were used in the preparation of acyclic N,N′-diacylhydrazines (5a–d)—precursors of 1,3,4-oxadiazoles containing alkyl groups (Scheme 3). The substitution reaction of 4-nitrobenzoyl chloride (4d) with acid hydrazides (3a–c) was carried out in dry diethyl ether at room temperature. The crude products (5a–c) precipitated after the addition of 4-nitrobenzoyl chloride (4d) into the reaction mixture, which was removed by filtration and washed with an aqueous solution of sodium carbonate (Na₂CO₃) to eliminate the hydrogen chloride (HCl) residue. Issues arose due to the effective removal of water from propionic acid hydrazide after the reaction of hydrazinolysis. Thus, for the synthesis of N′-propionyl-4′-nitrobenzohydrazide (5d), the reverse variant was used, in which 4-nitrobenzoic acid hydrazide (3d) and propanoyl chloride (4e) were applied in an analogous procedure. As a result of the reactions performed, five N′-alkanoyl-4-nitrobenzohydrazides were obtained with varying yields (5a–e, 37–90%,

Table 1. Derivatives of N′-alkanecarbonyl-4-nitrobenzohydrazide (5a–d) and 4-amino-N′-heptanoylbenzohydrazide (5e) derived from hydrazides and acid chlorides.

Entry	R 1	Acid Chloride	Product	Yield a [%]
1	C4H9	4-NO2-C6H4-COCl	5a	90
2	C6H13	4-NO2-C6H4-COCl	5b	88
3	C15H31	4-NO2-C6H4-COCl	5c	85
4	C2H5	4-NO2-C6H4-COCl	5d	37
5	C6H13	4-NH2-C6H4-COCl	5e	75

^a Isolated yields in respect to hydrazide 3.

).

The investigation of the cyclization of N,N′-diacylhydrazines (5a–d) to the corresponding 2-alkyl-1,3,4-oxadiazoles (6a–d) was conducted by first using N′-heptanoyl-4-nitrobenzohydrazide (5b) and phosphorus oxychloride (POCl₃) as they have been previously successfully applied to the synthesis of 2,5-diaryl derivatives of 1,3,4-oxadiazole [49].

The procedures were tested using an inert hydrocarbon solvent such as toluene (

Table 2. Optimization of the cyclization reaction of N′-heptanoyl-4-nitrobenzohydrazide (5b) to afford 2-hexyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6b).

Entry	Cyclization Reagent	Solvent	Temperature a [°C]	Time [h]	Yield b [%]
1	POCl3	toluene	80	8	30
2	POCl3	toluene	reflux	8	40
3	POCl3	-	reflux	24	47
4	SOCl2	toluene	80	8	55
5	SOCl2	-	reflux	8	70
6	SOCl2	-	reflux	24	78
7	P2O5	-	reflux	1	65
8	P2O5	toluene	reflux	1	70
9	P2O5	toluene	reflux	1.5	80

^a Conventional heating in oil bath. ^b Isolated yields of 6b in respect to compound 5b.

, Entries 1–2) and solvent-free (Table 2, Entry 3). When compound 5b was heated in excess POCl₃, acting both as a cyclodehydrating agent and solvent, the desired product 6b was generated in a moderate yield of 47% (Table 2, Entry 3). Subsequently, thionyl chloride (SOCl₂) was examined, providing better results (78%); however, the reaction time was longer (Table 2, Entry 6). Among the studied cyclodehydrating agents, diphosphorus pentoxide (P₂O₅) in toluene gave the best results, generating product 6b in a high yield of 80% after a short reaction time (Table 2, Entry 9). The elaborated conditions were used in the cyclization of N,N′-diacylhydrazines (5a–d, Scheme 4). Heating compounds 5a–d in excess P₂O₅ and dry toluene, followed by processing of the post-reaction mixture, gave 2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles 6a–d in high yields (78–97%,

Table 3. 2-Alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles (6a–d) and their reduced products—4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines (7a–d).

Entry	R1	Product 6	Product 7
		Yield a [%]	Yield b [%]
1	C4H9 (a)	80	91
2	C6H13 (b)	82	83
3	C15H31 (c)	78	88
4	C2H5 (d)	97	96

^a Isolated yields in respect to compound 5. ^b Isolated yields in respect to compound 6.

).

Next, the synthesized aromatic nitro derivatives were reduced. Since compounds 6a–d bear two units sensitive to reducing agents, the 1,3,4-oxadiazole ring, and nitro group (NO₂), the reducing agent, and the environment had to be specifically tailored to achieve selective reduction. Literature reports show the reduction of 2-(4-nitrophenyl)-1,3,4-oxadiazole derivatives by catalytic hydrogenation over Pd/C [50], or using SnCl₂ in methanol [51], Na₂S in water [52], or Fe/NH₄Cl in ethanol [53]. However, the latter methods require long reaction times and usually harsh conditions. The first reduction reaction studied involved a typical reduction system: iron filings in a concentrated HCl solution (Scheme 4). Heating 2-hexyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6b) in ethanol for 2 h reduced the nitro group on the benzene ring, and at the same time, the 1,3,4-oxadiazole core underwent ring opening. Hence, the main reaction product was a reduced acyclic 4-amino-N′-heptanoylbenzohydrazide (5e, 65%, Scheme 4). To confirm the identity of product 5e, it was also prepared by a previously presented method using heptane hydrazide 3b and 4-aminobenzoyl chloride (4f, Scheme 3), and both products were compared using spectroscopic analyses. Another reduction attempt utilized glacial acetic acid, representing a group of lower-strength organic acids. The heating of compound 6b with iron filings in glacial acetic acid for several hours promoted the reduction of the nitro group, producing derivative 4-(5-hexyl-1,3,4-oxadiazol-2-yl)aniline (7b) in a good yield (70%, Scheme 4). A literature report [54] examined the selective reduction of 2-(4-nitrophenyl)thiophene using sodium borohydride (NaBH₄) and hydrated tin chloride (SnCl₂·2H₂O). This approach was examined using 2-phenyl-1,3,4-oxadiazole derivatives substituted with the nitro group. To our delight, the reduction of derivative 6b occurred selectively, where reaction occurred without destruction of the aromatic benzene and 1,3,4-oxadiazole rings at room temperature within 1 h (83%, Table 3, Entry 2). Owing to the mild reaction conditions, short reaction time, high yield, and relatively simple method of isolating the final product, this procedure was used for the synthesis of the remaining reduced derivatives 7a, 7c–d. As a result, we obtained a series of 4-(1,3,4-oxadiazol-2-yl)anilines substituted with alkyl groups of different lengths at position 2 of the 1,3,4-oxadiazole ring (7a–d) in high yields of 83–96% (Table 3).

The prepared extended primary aromatic amines were used to study the synthesis of new azo moieties via the diazotization of the selected 4-(1,3,4-oxadiazol-2-yl)anilines (7a–b, 7d), and the subsequent coupling of the resulted diazonium salts with phenol, resorcinol, and N,N-dimethylaniline (Scheme 5).

The first step involved the diazotization of the aniline derivative (7a–b, 7d) dissolved in concentrated H₂SO₄ with a nitrosyl cation, which was generated in situ from NaNO₂ in such a medium, at temperatures of 0–5 °C. Urea was introduced in the final stage to eliminate excess nitrous acid in the post-reaction mixture. The obtained diazonium salts were used in the coupling sequence with three benzene derivatives substituted with electron-donating groups: phenol (X = OH, Y = H, series A), resorcinol (X = OH, Y = OH, series B), and N,N-dimethylaniline (X = N(CH₃)₂, Y = H, series C). The reactions with acidic coupling agents (phenol, resorcinol) were conducted using 20% aqueous NaOH, while for N,N-dimethylaniline, aqueous ethanol served as the reaction medium. The coupling reaction was conducted at a low temperature (0–5 °C) to avoid the decomposition of the unstable diazonium salts. The resulting azo compounds were precipitated from the post-reaction mixture via neutralization with aqueous NaOH solution, which was then removed by filtration, washed with water, and air-dried. This approach generated a series of new 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazoles (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) in satisfactory yields (75–93%,

Table 4. Three series of 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazoles (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) derived from 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines (7a–b, 7d).

Entry	Product	R1	X	Y	Yield a [%]
1	8a	C4H9	OH	H	80
2	8b	C6H13	OH	H	78
3	8d	C2H5	OH	H	75
4	9a	C4H9	OH	OH	93
5	9b	C6H13	OH	OH	91
6	9d	C2H5	OH	OH	90
7	10a	C4H9	N(CH3)2	H	89
8	10b	C6H13	N(CH3)2	H	84
9	10d	C2H5	N(CH3)2	H	87

^a Isolated yields with respect to the appropriate reagent (7a–b, 7d).

). However, among them, the simplest isolation methodology that provided the highest yields involved resorcinol (90–93%, Entries 4–6, Table 4). Generally, 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazoles are red-brownish substances except for one derivative: 4-{[4-(5-butyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}-N,N-dimethylaniline (10b), which was a dark green solid with a high melting point of 270 °C. They were highly soluble in acetone, DMSO, Et₂O, isopropanol, and toluene, and insoluble in water and hexane. Importantly, all nine synthesized derivatives were new compounds, not yet described in the literature.

The new intermediates and the final phenylazo compounds (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) were identified using classical spectroscopic methods (¹H-NMR, ¹³C-NMR, UV-Vis, FT-IR, and HRMS; see Supplementary Materials). All ¹H-NMR spectra of the synthesized azo dyes showed the presence of four signals (series A, series C) or five signals (series B) in the aromatic range of 6.35−8.16 ppm, attributed to the protons of the two benzene rings situated at the azo linkage −N=N−. The proton signals related to the alkyl groups located at position 2 of the 1,3,4-oxadiazole were found more upfield at 0.87−2.98 ppm. The number of signals depended on the length of the alkyl chain. For ethyl substituted derivatives (R¹ = C₂H₅, 8d, 9d, 10d), there were two signals: a triplet at ca. 1.35 ppm and a quartet at ca. 2.97 ppm. For butyl substituted derivatives (R¹ = C₄H₉, 8a, 9a, 10a), four signals were observed: a triplet representing the terminal -CH₃ group at 0.94 ppm, a quintet at 1.77 ppm, a sextet at 1.41 ppm, and a triplet at 2.95 ppm of internal -CH₂- groups. Finally, for hexyl substituted derivatives (R¹ = C₆H₁₃, 8b, 9b, 10b), four signals were observed: a triplet representing the terminal -CH₃ group at 0.87 ppm, a multiplet of three -CH₂- groups at 1.30−1.39 ppm, and a quintet and triplet representing the internal -CH₂- groups at ca. 1.78 ppm and 2.95 ppm, respectively. The characteristic hydroxyl group in series A (X = OH, 8a–b, 8d) from the introduced 4-hydroxyphenyl group appeared as a singlet at ca. 10.45 ppm. In the spectra of series B (X = OH, Y = OH, 9a–b, 9d), two characteristic hydroxyl groups were visible as two singlets at 10.71 ppm and 12.24 ppm, respectively, while in series C (X = N(CH₃)₂, 10a–b, 10d) that represented the N,N-dimethylamino group, they appeared in the range of 2.91–3.36 ppm. In the ¹³C-NMR spectra of the synthesized azo dyes, the characteristic peaks from 1,3,4-oxadiazole carbon atoms C-2 and C-5 were observed at 163.26−163.87 ppm and 166.79−167.55 ppm, respectively. The carbon atoms from two additional benzene rings were found at 102.98−164.63 ppm, while the alkyl groups appeared at 10.4–30.5 ppm. The signal related to the N,N-dimethylamino group from series C was observed at ca. 48.5 ppm. The formation of 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazoles (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) was also confirmed by HRMS analysis (see Materials and Methods). The FT-IR spectra of intermediates 5a–e, 6a–d, and 7a−d and the three series of phenylazo derivatives (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) were found between 4000 and 480 cm⁻¹ and further confirmed the changes occurring within the individual functional groups during the reaction sequences. The characteristic strong stretching vibrations of the carbonyl groups in N′-alkanoyl-4-nitrobenzohydrazides (5a–d) visible at 1589–1592 cm⁻¹ disappeared during the cyclization to 2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles (6a–d). The two sharp stretching bands of the nitro group connected directly to the benzene ring occurred both in acyclic precursors 5a–d at 1510–1520 cm⁻¹ and 1343–1349 cm⁻¹ and in its cyclic derivatives 6a–d at 1515–1519 cm⁻¹ and 1338–1348 cm⁻¹, respectively. During the reduction of 2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles (6a–b, 6d) to the corresponding 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines (7a–b, 7d), the bands mentioned above disappeared, and characteristic stretching modes for the primary aromatic amine appeared at 3446–3413 cm⁻¹, 3327–3338 cm⁻¹, and 3213–3218 cm⁻¹. The latter one showed the possible presence of hydrogen bonding in compounds 7a–b, 7d. The subsequent diazotization/coupling sequence led to the disappearance of the stretching vibrations of the amino group in the spectra of all azo compounds (series A–C). Instead of three representative bands, we observed a broad band of variable intensity in the range of 3100–3500 cm⁻¹, resulting from stretching vibrations of the hydroxyl groups in two series of azo compounds (8a–b, 8d, series A and 9a–b, 9d, series B).

The UV-Vis spectra of 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazoles (8a–b, 8d; 9a–b, 9d; 10a–b, 10d) registered in aqueous methanol within the range of 240 nm to 600 nm showed the presence of two or even three absorption bands resulting from n→π* and π→π* electronic transitions (Figure 2).

The influence of the alkyl chain’s length at position 2 of 5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazole dyes within series A–C on the location of the absorption maxima was rather small and varied from 2 to 8 nm for the corresponding absorption bands. In addition, Figure 3 shows the UV-Vis absorption spectra of the three series of azo dyes (Figure 3a–c) measured both in acidic aqueous methanol (A) and basic aqueous methanol (B) solutions. The presence of hydroxyl and dimethylamino groups in the studied azo compounds rendered the compounds susceptible to acid–base interactions.

Considerable changes in the spectra of the ionized form in basic media (NaOH, aqueous methanol, —) and acidic media (HCl, aqueous methanol, —) were observed, especially for the long-wavelength bands. In the case of series A derived from phenol (Figure 3a, 8a–b, 8d), alkalization resulted in a batochromic shift of the n→π* band by 66−80 nm, which was accompanied by a slight hypochromic effect. A weaker batochromic shift (36−44 nm) of the n→π* band was also observed in series B (Figure 3b, 9a–b, 9d) containing a 2,4-dihydroxyphenyl group. However, the spectra of the ionized forms of the studied compounds 9a–b, and 9d registered in basic media, showed a considerable hyperchromic effect compared to the neutral forms in acidic media. Finally, in the case of series C derived from N,N-dimethylaniline (Figure 3c, 10a–b, 10d), acidification caused a marked batochromic shift of the n→π* band by 84−88 nm, which was accompanied by a slight hyperchromic effect.

3. Materials and Methods

3.1. General Information

All reagents were purchased from commercial sources and used without further purification. Melting points were measured using a Stuart SMP3 melting point apparatus (Staffordshire, UK). NMR spectra were recorded at 25 °C using an Agilent spectrometer (Agilent Technologies, Waldbronn, Germany) at 400 MHz for ¹H and 100 MHz for ¹³C, and a Varian spectrometer (Palo Alto, CA, USA) at 600 MHz for ¹H and 151 MHz for ¹³C, respectively, with CDCl₃ or DMSO as the solvent and TMS as the internal standard. UV-Vis spectra were recorded in methanol and dichloromethane solutions (2.0 × 10⁻⁵ M) with a Jasco V-650 spectrophotometer (Jasco International CO., Tokyo, Japan). High-resolution mass spectra were acquired using a Waters ACQUITY UPLC/Xevo G2QT instrument (Waters Corporation, Milford, MA, USA). Thin-layer chromatography (TLC) was performed using silica gel 60 F254 (Merck, Merck KGaA, Darmstadt, Germany) on thin-layer chromatography plates, with Benzene:AcOEt (1:3), MeOH:CHCl₃ (1:4), or Hexane:AcOEt (1:2) as the mobile phase.

3.2. Synthesis and Characterization

3.2.1. General Procedure for the Synthesis of Methyl Esters (2a–d)

A solution of carboxylic acid (1a–d, 0.25 mol), methanol (100 mL, 2.5 mol), and concentrated sulfuric acid (5 mL) was refluxed until the acid was fully consumed (monitored by TLC, 4–12 h). After cooling, the mixture was neutralized with NaHCO₃ and extracted with 3 × 20 mL of dichloromethane. The organic phase was dried over MgSO₄ and concentrated on a rotary evaporator. The crude methyl esters (2a–d) were used for subsequent reactions without additional purification.

• Methyl valerate (2a). The product was obtained as a colorless liquid (24.40 g, 84%) [55].
• Methyl heptanoate (2b). The product was obtained as a colorless liquid (34.20 g, 95%) [56].
• Methyl palmitate (2c). The product was obtained as a white solid (54.50 g, 85%); mp 29–30 °C (28–30 °C [57]).
• Methyl 4-nitrobenzoate (2d). The product was obtained as yellow solid (39.80 g, 88%); mp 101–102 °C (99–100 °C [58]).

3.2.2. General Procedure for the Synthesis of Acid Hydrazides (3a–d)

A solution of methyl ester (2a–d, 0.20 mol), hydrazine hydrate (28 mL, 0.55 mol), and methanol (100 mL) was refluxed until the ester was fully consumed (monitored by TLC, 4–19 h). After cooling, the mixture was concentrated on a rotary evaporator. The crude hydrazides were crystallized from ethanol or methanol.

• Valeryl hydrazide (3a). The product was obtained as a white solid (13.70 g, 59%); mp 63–64 °C (50.5–51.5 °C [59]).
• Heptanehydrazide (3b). The product was obtained as a white solid (23.00 g, 80%); mp 87–88 °C (82–84 °C [60]).
• Palmitohydrazide (3c). The product was obtained as a white solid (43.80 g, 81%); mp 112–114 °C (112–113 °C [61]).
• 4-Nitrobenzohydrazide (3d). The product was obtained as a yellow solid (30.80 g, 85%); mp 220–221 °C (217–218 °C [62]).

3.2.3. General Procedure for the Synthesis of Acid Chlorides (4d–f)

A mixture of carboxylic acid (1d–f, 0.20 mol) and PCl₅ (41.65 g, 0.20 mol) or SOCl₂ (29 mL, 0.40 mol) was refluxed until the acid was fully consumed (monitored by TLC, 2–20 h). After cooling, the mixture was concentrated using a rotary evaporator. The crude acid chlorides (4d–f) were distilled under reduced pressure.

• Propionyl chloride (4e). The product was obtained as a colorless liquid (14.80 g, 80%); bp 78–80 °C (bp 77–79 °C [63]).
• 4-Aminobenzoyl chloride (4f). The product was obtained as a yellow solid (27.30 g, 90%); bp 168–170 °C/33 mm Hg, mp 35–36 °C (bp 168–170 °C/33 mm Hg, mp 31–39 °C [64]).
• 4-Nitrobenzoyl chloride (4d). The product was obtained as a yellow solid (31.50 g, 85%); bp 175–180 °C/25 mm Hg, mp 71–74 °C (bp 194–196 °C/25 mm Hg, mp 71–73 °C [65]).

3.2.4. General Procedure for the Synthesis of N,N′-Diacylhydrazines (5a–e)

Hydrazide (3a–d, 0.02 mol) was suspended in dry diethyl ether (30 mL); then, acid chloride (4d–f, 0.02 mol) dissolved in dry diethyl ether (10 mL) was carefully added at room temperature. The reaction mixture was agitated at room temperature for approx. 1 h, followed by the addition of a Na₂CO₃ solution (2.12 g, 0.02 mol) in water (15 mL). The mixture was agitated for 30 min, and the white precipitate was filtered, washed with diethyl ether (20 mL), and air dried.

• 4-Nitro-N′-pentanoylbenzohydrazide (5a). The product was obtained as a white solid (4.70 g, 90%); mp 187–188 °C (188–190 °C [52]). UV-Vis (CH₃OH) λ_max (logε) 202 (4.19), 262 (4.12) nm.
• N′-Heptanoyl-4-nitrobenzohydrazide (5b). The product was obtained as awhite solid (5.30 g, 88%); mp 181–182 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H, NH), 9.96 (s, 1H, NH), 8.34 (d, 2H, J = 8.8 Hz, Ar), 8.09 (d, 2H, J = 8.8 Hz, Ar), 2.20 (t, 2H, J = 7.2 Hz, CH₂), 1.54 (qui, 2H, J = 7.2 Hz, CH₂), 1.29−1.34 (m, 6H, CH₂), 0.88 (t, 3H, J = 6.8 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 171.5, 163.9, 149.3, 138.2, 128.9, 123.6, 33.2, 31.0, 28.2, 25.0, 22.0, 13.9; IR (ATR) ν_max: 3194 (N-H), 3030, 2960, 2926, 2854, 1609 (N-H), 1592 (N-H), 1509 (N-O), 1349 (C-N), 1212, 867, 847 (N-O), 716 cm⁻¹; HRMS calcd for (C₁₄H₁₉N₃O₄+H⁺): 294.1454; found: 294.1458. UV-Vis (CH₃OH) λ_max (logε) 214 (3.98), 266 (4.09) nm.
• 4-Nitro-N′-hexadecanoylbenzohydrazide (5c). The product was obtained as a white solid (7.10 g, 85%); mp 160–161 °C). IR (ATR) ν_max: 3211 (N-H), 2917, 2848, 1609 (N-H), 1592 (N-H), 1574, 1522 (N-O), 1464, 1349 (C-N), 1210, 872, 846 (N-O), 719 cm⁻¹; HRMS calcd for (C₂₃H₃₆N₃O₄+H⁺): 420.2862; found: 420.2843.
• N′-Propionyl-4′-nitrobenzohydrazide (5d). The product was obtained as a white solid (1.80 g, 37%); mp 192–193 °C (203–205 °C [52]). UV-Vis (CH₃OH) λ_max (logε) 262 (4.11) nm.
• 4-Amino-N′-heptanoylbenzohydrazide (5e). The product was obtained as a white solid (3.90 g, 75%); mp 188–189 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.75 (s, 1H, NH), 9.60 (s, 1H, NH), 7.59 (d, 2H, J = 8.4 Hz, Ar), 6.53 (d, 2H, J = 8.4 Hz, Ar), 5.69 (s, 2H, NH₂), 2.14 (t, 2H, J = 7.6 Hz, CH₂), 1.51 (qui, 2H, J = 7.6 Hz, CH₂), 1.21–1.33 (m, 6H, CH₂), 0.87 (t, 3H, J = 6.8 Hz, CH₃), ¹³C NMR (100 MHz, DMSO-d₆): δ 171.6, 165.5, 152.1, 129.0, 119.0, 112.5, 33.3, 31.0, 28.2, 25.1, 22.0, 13.4; IR (ATR) ν_max: 3463 (N-H), 3355 (N-H), 3209 (N-H), 2924, 1695, 1598 (N-H), 1486, 1307, 1180, 724 cm⁻¹; HRMS calcd for (C₁₄H₂₁N₃O₂+H⁺): 264.1712; found: 264.1722. UV-Vis (CH₃OH) λ_max (logε) 288 (4.38) nm.

3.2.5. General Procedure for the Synthesis of 2-Alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles (6a–d)

N,N′-Diacylhydrazine (5a–d, 0.01 mol), phosphorus pentaoxide (6.9 g), and dry toluene (70 mL) were refluxed in an oil bath until the N,N′-diacylhydrazine was fully consumed (monitored by TLC, 1–3 h). Then, the solvent was evaporated on a rotary evaporator, and the resulting precipitate was dissolved in water (70 mL) and extracted with ethyl acetate or chloroform (3 × 30 mL). The organic phase was dried over anhydrous MgSO₄, and the solvent was evaporated on a rotary evaporator. The crude products (6a–d) were used without additional purification.

• 2-Butyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6a). The product was obtained as a white solid (1.98 g, 80%); mp 66–67 °C (130–131 °C [66]). ¹H-NMR (400 MHz, CDCl₃): δ 8.36 (d, 2H, J = 8.8 Hz, Ar), 8.23 (d, 2H, J = 8.8 Hz, Ar), 2.98 (t, 2H, J = 7.6 Hz, CH₂), 1.85 (qui, 2H, J = 7.6 Hz, CH₂), 1.46 (sextet, 2H, J = 7.2 Hz, CH₂), 1.00 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, CDCl₃): δ 168.1, 163.0, 149.4, 129.6, 127.6, 124.0, 28.5, 25.2, 22.1, 13.5; IR (ATR) ν_max: 3109, 2933, 2872, 1738 (N=C), 1607, 1562, 1517 (N-O), 1348, 1233 (-O-), 1106, 867 (N-O), 714cm⁻¹; HRMS calcd for (C₁₂H₁₃N₃O₃+H⁺): 248.1035; found: 248.1007; UV-Vis (CH₃OH) λ_max (logε) 204 (4.68), 286 (4.40) nm.
• 2-Hexyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6b). The product was obtained as a white solid (2.26 g, 82%); mp 60–61 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ, 8.41 (d, 2H, J = 8.8 Hz, Ar), 8.23 (d, 2H, J = 8.8 Hz, Ar), 2.97 (t, 2H, J = 7.6 Hz, CH₂), 1.76 (qui, 2H, J = 7.6 Hz, CH₂), 1.30−1.38 (m, 6H, CH₂), 0.87 (t, 3H, J = 7.6 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.9, 162.5, 149.0, 129.0, 127.7, 124.6, 30.7, 27.9, 25.7, 24.6, 21.9, 13.8; IR (ATR) ν_max: 3110, 2916, 2851, 1739 (N=C), 1606, 1567, 1518 (N-O), 1338, 1231 (-O-), 1106, 867 (N-O), 710 cm⁻¹; HRMS calcd for (C₁₄H₁₇N₃O₃+H⁺): 276.1348; found: 276.1351; UV-Vis (CH₃OH) λ_max (logε) 218 (4.02), 288 (4.26) nm.
• 2-Pentadecyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6c). The product was obtained as a white solid (3.10 g, 78%); mp 89–90 °C). ¹H-NMR (400 MHz, CDCl₃): δ 8.36 (d, 2H, J = 8.8 Hz, Ar), 8.22 (d, 2H, J = 8.8 Hz, Ar), 2.96 (t, 2H, J = 7.2 Hz, CH₂), 1.87 (qui, 2H, J = 7.2 Hz, CH₂), 1.25–1.47 (m, 24H, CH₂), 0.88 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, CDCl₃): δ 168.2, 163.0, 149.4, 129.6, 127.6, 124.3, 31.9, 29.65, 29.64, 29.62, 29.61, 29.6, 29.5, 29.4, 29.3, 29.1, 29.0, 26.5, 25.5, 22.7, 14.1; IR (ATR) ν_max: 3120, 2914, 2848, 1738 (N=C), 1607, 1567, 1519 (N-O), 1342, 1218 (-O-), 1107, 868 (N-O), 710 cm⁻¹; HRMS calcd for (C₂₃H₃₅N₃O₃+H⁺): 402.2757; found: 402.2755. UV-Vis (CH₂Cl₂) λ_max (logε) 294 (4.25) nm.
• 2-Ethyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (6d). The product was obtained as a white solid (2.10 g, 97%); mp 132–133 °C (131–135 °C [52]). UV-Vis (CH₃OH) λ_max (logε) 286 (4.47) nm.

3.2.6. General Procedure for the Synthesis of 4-(5-Alkyl-1,3,4-oxadiazol-2-yl)anilines (7a–d)

5-Alkyl-2-(4-nitrophenyl)-1,3,4-oxadiazole (6a–d, 0.01 mol), SnCl₂∙2H₂O (11.3 g, 0.05 mol), and ethanol (40 mL) were heated until a homogenous solution was achieved. The mixture was allowed to cool and a suspension of NaBH₄ (0.5 g, 13 mmol) in ethanol (25 mL) was added dropwise. It was agitated at room temperature for 1–3 h (monitored by TLC). Then, the mixture was alkalized with 20% NaOH, the precipitate was removed by filtration under reduced pressure, and the filtrate was concentrated on a rotary evaporator. It was extracted with chloroform (3 × 25 mL), dried over MgSO₄, filtered, and the solvent was evaporated, yielding the crude products (7a–d).

• 4-(5-Butyl-1,3,4-oxadiazol-2-yl)aniline (7a). The product was obtained as a brown solid (1.98 g, 91%); mp 103–104 °C (119–122 °C [52]). ¹H-NMR (400 MHz, CDCl₃): δ 7.80 (d, 2H, J = 8.4 Hz, Ar), 6.71 (d, 2H, J = 8.8 Hz, Ar), 4.06 (s, 2H, NH₂), 2.88 (t, 2H, J = 7.6 Hz, CH₂), 1.77 (qui, 2H, J = 7.2 Hz, CH₂), 1.41 (sextet, 2H, J = 7.2 Hz, CH₂), 0.97 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, CDCl₃): δ 166.0, 165.0, 149.4, 128.4, 114.6, 112.4, 28.7, 25.1, 22.1, 13.6; IR (ATR) ν_max: 3413 (N-H), 3328 (N-H), 3215, 2960, 2960, 2960, 1606 (N-H), 1497, 1315(C-N), 1173 (C-O), 827 cm⁻¹; HRMS calcd for (C₁₂H₁₅N₃O+H⁺): 218.1293; found: 218.1275; UV-Vis (CH₃OH) λ_max (logε) 202 (4.13), 218 (4.01), 306 (4.36) nm.
• 4-(5-Hexyl-1,3,4-oxadiazol-2-yl)aniline (7b). The product was obtained as a brown solid (2.20 g, 83%); mp 109–110 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.61 (d, 2H, J = 8.4 Hz, Ar), 6.66 (d, 2H, J = 8.4 Hz, Ar), 5.87 (s, 2H, NH₂), 2.85 (t, 2H, J = 7.2 Hz, CH₂), 1.70 (qui, 2H, J = 7.2 Hz, CH₂), 1.29−1.36 (m, 6H, CH₂), 0.86 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 165.6, 164.9, 152.5, 128.0, 114.0, 110.5, 31.2, 28.4, 26.3, 25.0, 22.3, 14.2; IR (ATR) ν_max: 3446 (N-H), 3339 (N-H), 3219, 2940, 1738, 1588, 1497, 1319 (C-N), 1176 (C-O), 835 cm⁻¹; HRMS calcd for (C₁₄H₁₉N₃O+H⁺): 246.1606; found: 246.1623. UV-Vis (CH₃OH) λ_max (logε) 302 (4.43) nm.
• 4-(5-Pentadecyl-1,3,4-oxadiazol-2-yl)aniline (7c). The product was obtained as a yellow solid (3.30 g, 88%); mp 103–104 °C). ¹H-NMR (600 MHz, CDCl₃): δ 7.81 (d, 2H, J = 8.4 Hz, Ar), 6.72 (d, 2H, J = 8.4 Hz, Ar), 4.04 (s, 2H, NH₂), 2.87 (t, 2H, J = 7.8 Hz, CH₂), 1.82 (qui, 2H, J = 7.8 Hz, CH₂), 1.20−1.42 (m, 24H, CH₂), 0.88 (t, 3H, J = 7.8 Hz, CH₃); ¹³C-NMR (151 MHz, CDCl₃): δ 166.0, 165.0, 149.4, 128.4, 114.6, 112.5, 31.9, 29.66, 29.65, 29.64, 29.62, 29.61, 29.6, 29.4, 29.3, 29.1, 29.0, 26.7, 25.4, 22.7, 14.1; IR (ATR) ν_max: 3337 (N-H), 2916, 2849, 1738, 1607, 1557, 1500, 1378 (C-N), 1178 (C-O), 842 cm⁻¹; HRMS calcd for (C₂₃H₃₇N₃O+H⁺): 372.3015; found: 372.3009. UV-Vis (CH₂Cl₂) λ_max (logε) 292 (4.55) nm.
• 4-(5-Ethyl-1,3,4-oxadiazol-2-yl)aniline (7d). The product was obtained as a yellow solid (1.80 g, 96%); mp 140–141 °C (138–142 °C [52]). UV-Vis (CH₃OH) λ_max (logε) 302 (4.48) nm.

3.2.7. Reduction of 2-Hexyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (7b) with Iron Filings in Concentrated HCl

5-Hexyl-2-(4-nitrophenyl)-1,3,4-oxadiazole (6b, 3.6 mmol), iron filings (1.23 g; 0.022 mol), and concentrated HCl (4 mL) were heated in ethanol (40 mL) under reflux for 2 h (monitored by TLC). The mixture was alkalized with 20% NaOH, the precipitate was removed by filtration under reduced pressure, and the filtrate was concentrated on a rotary evaporator. Then, it was extracted with chloroform (3 × 25 mL), dried over MgSO₄, filtered, and the solvent was evaporated on a rotary evaporator, yielding crude product 5e as a white solid (0.62 g, 65%); mp 188–189 °C.

3.2.8. Reduction of 2-Hexyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (7b) with Iron Filings in Glacial Acetic Acid

5-Hexyl-2-(4-nitrophenyl)-1,3,4-oxadiazole (6b, 3.6 mmol), iron filings (1.23 g, 0.022 mol), and glacial acetic acid (4 mL) were heated under reflux for 6 h (monitored by TLC). Then, the mixture was alkalized with 20% NaOH, the precipitate was removed by filtration under reduced pressure, and the filtrate was concentrated on a rotary evaporator. It was extracted with chloroform (3 × 25 mL), dried over MgSO₄, filtered, and the solvent was evaporated on a rotary evaporator, yielding crude product 7b as a brown solid (0.62 g, 70%); mp 109–110 °C.

3.2.9. General Procedure for the Synthesis of 4-{[4-(5-Alkyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl} phenol (8a–b, 8d)

The appropriate 5-alkyl-2-(4-aminophenyl)-1,3,4-oxadiazole (7a–b, 7d, 4.61 mmol) was added to concentrated H₂SO₄ (7 mL), and the suspension was heated to 50 °C in a water bath and agitated until complete dissolution. Then, the mixture was cooled in an ice-salt bath to 0 °C, and NaNO₂ solution (5.1 mmol, 0.35 g) in water (20 mL) was slowly added while maintaining the temperature at 0−5 °C. The mixture was stirred for 1 h, and urea was added to deactivate the excessive nitrous acid. Separately, phenol (4.61 mmol, 0.43 g) was dissolved in 20% NaOH (20 mL) and added dropwise to the diazonium salt solution. The mixture was agitated for 1 h at 0−5 °C. It was neutralized using 20% NaOH solution. The colored solid was washed with water (2 × 20 mL) and air-dried. The crude product (8a–b, 8d) was additionally purified by column chromatography on silica gel using the appropriate mobile phase.

• 4-{[4-(5-Butyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}phenol (8a). The product was obtained as a dark brown solid (1.19 g, 80%). It was purified by column chromatography (MeOH:CHCl₃, 1:4, v/v); R_f = 0.71; mp 95–98 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H, OH), 8.14 (d, 2H, J = 8.4 Hz, Ar), 7.97 (d, 2H, J = 8.4 Hz, Ar), 7.85 (d, 2H, J = 8.8 Hz, Ar), 6.97 (d, 2H, J = 8.8 Hz, Ar), 2.95 (t, 2H, J = 7.2 Hz, CH₂), 1.77 (qui, 2H, J = 7.2 Hz, CH₂), 1.41 (sextet, 2H, J = 7.2 Hz, CH₂), 0.94 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.1, 163.4, 161.6, 153.6, 145.3, 129.3, 127.5, 125.3, 124.6, 116.1, 27.9, 24.3, 21.5, 13.4; IR (ATR) ν_max: 3106 (O-H), 2958, 2873, 1586, 1466 (N=N), 1226 (C-OH), 1192, 1138, 849, 746 cm⁻¹; HRMS calcd for (C₁₈H₁₈N₄O₂+H⁺): 323.1508; found: 323.1513; UV-Vis (CH₃OH) λ_max (logε) 268 (4.03), 366 (4.26) nm.
• 4-{[4-(5-Hexyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}phenol (8b). The product was obtained as a light brown solid (1.26 g, 78%). It was purified by column chromatography (Benzene:AcOEt, 1:3, v/v); R_f = 0.63; mp 125–126 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H, OH), 8.14 (d, 2H, J = 8.4 Hz, Ar), 7.98 (d, 2H, J = 8.4 Hz, Ar), 7.85 (d, 2H, J = 8.8 Hz, Ar), 6.97 (d, 2H, J = 8.8 Hz, Ar), 2.95 (t, 2H, J = 7.6 Hz, CH₂), 1.78 (qui, 2H, J = 7.6 Hz, CH₂), 1.30–1.39 (m, 6H, CH₂), 0.87 (t, 3H, J = 6.8 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.1, 163.4, 161.6, 153.6, 145.3, 129.3, 127.5, 125.3, 124.6, 116.1, 30.7, 28.0, 25.7, 24.6, 21.9, 13.8; IR (ATR) ν_max: 3214 (O-H), 3054, 2924, 2854, 1586, 1464 (N=N), 1220 (C-OH), 1190, 1190, 1138, 850, 749 cm⁻¹; HRMS calcd for (C₂₀H₂₂N₄O₂+H⁺): 351.1821; found: 351.1819; UV-Vis (CH₃OH) λ_max (logε) 264 (3.80), 366 (4.17) nm.
• 4-{[4-(5-Ethyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}phenol (8d). The product was obtained as a brown solid (1.01 g, 75%). It was purified by column chromatography (Benzene: AcOEt, 1:3, v/v); R_f = 0,52; mp 185–188 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H, OH), 8.14 (d, 2H, J = 8.4 Hz, Ar), 7.97 (d, 2H, J = 8.4 Hz, Ar), 7.85 (d, 2H, J = 8.8 Hz, Ar), 6.97 (d, 2H, J = 8.8 Hz, Ar), 2.98 (q, 2H, J = 7.6 Hz, CH₂), 1.35 (t, 3H, J = 7.6 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 168.0, 163.4, 161.6, 153.6, 145.3, 129.3, 127.5, 125.3, 122.9, 116.0, 18.4, 10.4; IR (ATR) ν_max: 3187 (O-H), 2985, 1683, 1593, 1472 (N=N), 1227 (C-OH), 1099, 844, 755 cm⁻¹; HRMS calcd for (C₁₆H₁₄N₄O₂+H⁺): 295.1195; found: 295.1182; UV-Vis (CH₃OH) λ_max (logε) 262 (3.65), 362 (3.80) nm.

3.2.10. General Procedure for the Synthesis of 4-{[4-(5-Alkyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}benzene-1,3-diol (9a–b, 9d)

The appropriate 5-alkyl-2-(4-aminophenyl)-1,3,4-oxadiazole (7a–b, 7d, 4.61 mmol) was added to concentrated H₂SO₄ (7 mL), and the suspension was heated to 50 °C in a water bath and agitated until complete dissolution. Then, the mixture was cooled in an ice-salt bath to 0 °C, and NaNO₂ solution (5.1 mmol, 0.35 g) in water (20 mL) was slowly added, maintaining the temperature at 0−5 °C. The mixture was stirred for 1 h, and urea was added to deactivate the excessive nitrous acid. Separately, resorcinol (4.61 mmol, 0.51 g) was dissolved in 20% NaOH (20 mL) and added dropwise to the diazonium salt solution. The mixture was agitated for 1 h at 0−5 °C. It was neutralized using 20% NaOH solution. The colored solid was filtered under reduced pressure, washed with water (2 × 20 mL), and air-dried. The crude product (9a–b, 9d) was purified by column chromatography on silica gel using the appropriate mobile phase.

• 4-{[4-(5-Butyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}benzene-1,3-diol (9a). The product was obtained as a brown solid (1.45 g, 93%). It was purified by column chromatography (AcOEt:Hexane, 2:1, v/v); R_f = 0.42; mp 150–154 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H, OH), 10.69 (s, 1H, OH), 8.07 (d, 2H, J = 8.4 Hz, Ar), 7.99 (d, 2H, J = 8.4 Hz, Ar), 7.66 (d, 1H, J = 8.8 Hz, Ar), 6.47 (d, 1H, J = 8.8 Hz, Ar), 6.35 (s, 1H, Ar), 2.91 (t, 2H, J = 7.2 Hz, CH₂), 1.73 (qui, 2H, J = 7.2 Hz, CH₂), 1.37 (sextet, 2H, J = 7.2 Hz, CH₂), 0.90 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.5, 164.4, 163.9, 157.8, 152.9, 133.2, 129.5, 128.0, 124.5, 123.0, 110.0, 103.5, 28.3, 24.7, 22.00, 13.9; IR (ATR) ν_max: 2956 (O-H), 1601, 1472 (N=N), 1232 (C-OH), 737 cm⁻¹; HRMS calcd for (C₁₈H₁₈N₄O₃+H⁺): 339.1457; found: 339.1454; UV-Vis (CH₃OH) λ_max (logε) 262 (4.00), 400 (4.28) nm.
• 4-{[4-(5-Hexyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}benzene-1,3-diol (9b). The product was obtained as a red solid (1.54 g, 91%). It was purified by column chromatography (Benzene: AcOEt, 1:3, v/v); R_f = 0.55; mp 179–180 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.28 (s, 1H, OH), 10.72 (s, 1H, OH), 8.11 (d, 2H, J = 8.8 Hz, Ar), 8.02 (d, 2H, J = 8.8 Hz, Ar), 7.69 (d, 1H, J = 8.4 Hz, Ar), 6.51 (d, 1H, J = 8.4 Hz, Ar), 6.38 (d, 1H, J = 2.4 Hz, Ar), 2.94 (t, 2H, J = 7.2 Hz, CH₂), 1.77 (qui, 2H, J = 7.2 Hz, CH₂), 1.29–1.39 (m, 6H, CH₂), 0.87 (t, 3H, J = 7.2 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.0, 163.9, 163.4, 157.3, 152.4, 132.8, 129.1, 127.5, 124.1, 122.5, 109.6, 103.0, 30.7, 28.0, 25.7, 24.6, 21.9, 13.8; IR (ATR) ν_max: 3094 (O-H), 2951, 2927, 2853, 1591, 1472 (N=N), 1317, 1228 (C-OH), 846, 744 cm⁻¹; HRMS calcd for (C₂₀H₂₂N₄O₃+H⁺): 367.1770; found: 367.1747; UV-Vis (CH₃OH) λ_max (logε) 264 (4.19), 402 (4.49) nm.
• 4-{[4-(5-Ethyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}benzene-1,3-diol (9d). The product was obtained as a thick, dark red solid (1.27 g, 90%). It was purified by column chromatography (Hexane:AcOEt, 1:2, v/v); R_f = 0.38; mp 210–214 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.24 (s, 1H, OH), 10.71 (s, 1H, OH), 8.12 (d, 2H, J = 8.4 Hz, Ar), 8.03 (d, 2H, J = 8.4 Hz, Ar), 7.70 (d, 1H, J = 8.8 Hz, Ar), 6.51 (d, 1H, J = 8.8 Hz, Ar), 6.39 (s, 1H, Ar), 2.94 (q, 2H, J = 7.6 Hz, CH₂), 1.35 (t, 3H, J = 7.6 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.4, 164.6, 163.9, 157.3, 152.3, 132.8, 128.95, 127.5, 124.1, 122.5, 109.6, 103.0, 18.4, 10.4; IR (ATR) ν_max: 3340 (O-H), 1602, 1477 (N=N), 1242, 1235 (C-OH), 1108, 839 cm⁻¹; HRMS calcd for (C₁₆H₁₄N₄O₃+H⁺): 311.1144; found: 311.1145; UV-Vis (CH₃OH) λ_max (logε) 262 (3.35), 398 (3.68) nm.

3.2.11. General Procedure for the Synthesis of 4-{[4-(5-Alkyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}-N,N-dimethylaniline (10a–b, 10d)

The appropriate 5-alkyl-2-(4-aminophenyl)-1,3,4-oxadiazole (7a–b, 7d, 4.61 mmol) was added to concentrated H₂SO₄ (7 mL), and the suspension was heated to 50 °C in a water bath and agitated until complete dissolution. Then, the mixture was cooled in an ice-salt bath to 0 °C, and NaNO₂ solution (5.1 mmol, 0.35 g) in water (20 mL) was slowly added, maintaining the temperature at 0−5 °C. The mixture was stirred for 1 h, and urea was added to deactivate the excessive nitrous acid. Separately, N,N-dimethylaniline solution (4.61 mmol, 0.56 g) in ethanol (10 mL) was prepared and added dropwise to the agitated diazonium salt solution. The mixture was agitated for 1 h at 0−5 °C. It was neutralized by the addition of 20% NaOH solution. The colored solid was filtered under reduced pressure, washed with water (2 × 20 mL), and air-dried. The crude product (10a–b, 10d) was additionally purified by column chromatography on silica gel with the appropriate mobile phase.

• 4-{[4-(5-Butyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}-N,N-dimethylaniline (10a). The product was obtained as a dark green solid (1.43 g, 89%). It was purified by column chromatography (Hexane: AcOEt, 7:3, v/v) R_f = 0.22. mp 270–272 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.10 (d, 2H, J = 7.6 Hz, Ar), 7.92 (d, 2H, J = 6.8 Hz, Ar), 7.72 (d, 2H, J = 6.8 Hz, Ar), 6.85 (d, 2H, J = 7.6 Hz, Ar), 3.04 (s, 6H, CH₃), 2.85 (t, 2H, J = 6.4 Hz, CH₂), 1.75 (qui, 2H, J = 6.4 Hz, CH₂), 1.41 (sextet, 2H, J = 6.4 Hz, CH₂), 0.92 (t, 3H, J = 6.4 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.0, 163.1, 154.1, 152.9, 142.3, 128.6, 127.7, 127.4, 125.1, 111.9, 48.4, 28.7, 24.3, 21.5, 13.4; IR (ATR) ν_max: 2956 (CH₃), 2931, 2871, 1681, 1600, 1507, 1446 (N=N), 1363, 1136 (C-N), 1008, 822, 751, 692 cm⁻¹; HRMS calcd for (C₂₀H₂₃N₅O+H⁺): 350.1981; found: 350.1985; UV-Vis (CH₃OH) λ_max (logε) 254 (4.31), 432 (3.74) nm.
• 4-{[4-(5-Hexyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}-N,N-dimethylaniline (10b). The product was obtained as a dark red liquid (1.46 g, 84%). It was purified by column chromatography (Benzene:AcOEt, 1:3, v/v); R_f = 0.62. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.00 (d, 2H, J = 8.0 Hz, Ar), 7.59 (d, 2H, J = 7.2 Hz, Ar), 7.31 (d, 2H, J = 7.2 Hz, Ar), 6.70 (d, 2H, J = 8.0 Hz, Ar), 3.32 (s, 6H, CH₃), 2.92 (t, 2H, J = 7.2 Hz, CH₂), 1.76 (qui, 2H, J = 7.2 Hz, CH₂), 1.25–1.36 (m, 6H, CH₂), 0.87 (t, 3H, J = 7.6 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 166.7, 163.2, 154.9, 150.4, 142.7, 128.8, 128.1, 126.3, 125.9, 112.3, 49.3, 30.7, 27.9, 25.7, 24.5, 21.9, 13.8; IR (ATR) ν_max: 2927 (CH₃), 2857, 1682, 1599, 1495 (N=N), 1362, 1133 (C-N), 1011, 843, 751, 691 cm⁻¹; HRMS calcd for (C₂₂H₂₇N₅O+H⁺): 378.2294; found: 378.2271; UV-Vis (CH₃OH) λ_max (logε) 254 (4.26), 368 (3.62), 436 (3.49) nm.
• 4-{[4-(5-Ethyl-1,3,4-oxadiazol-2-yl)phenyl]diazenyl}-N,N-dimethylaniline (10d). The product was obtained as a dark red liquid (1.29 g, 87%). It was purified by column chromatography (Benzene:AcOEt, 1:3, v/v); R_f = 0.25. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.98 (d, 2H, J = 8.8 Hz, Ar), 7.64 (d, 2H, J = 8.4 Hz, Ar), 7.30 (d, 2H, J = 8.4 Hz, Ar), 6.66 (d, 2H, J = 8.8 Hz, Ar), 3.36 (s, 6H, CH₃), 2.95 (q, 2H, J = 4.8 Hz, CH₂), 1.32 (t, 3H, J = 4.8 Hz, CH₃); ¹³C-NMR (100 MHz, DMSO-d₆): δ 167.6, 163.3, 154.3, 151.1, 142.7, 128.1, 127.7, 126.3, 125.7, 111.9, 48.5, 19.7, 10.3; IR (ATR) ν_max: 3224, 2974 (CH₃), 1647, 1600, 1490 (N=N), 1363, 1170 (C-N), 1012, 820, 704 cm⁻¹; HRMS calcd for (C₁₈H₁₉N₅O+H⁺): 322.1668; found: 322.1622; UV-Vis (CH₃OH) λ_max (logε) 266 (4.22), 424 (3.63) nm.

4. Conclusions

In summary, we developed a multistep reaction procedure for the preparation of three series of novel azo compounds, which were the derivatives of 2-alkyl-5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazole. The key intermediate N′-alkanecarbonyl-4-nitrobenzohydrazides, obtained from the reaction of the corresponding acid chlorides and hydrazides, were successfully cyclized using phosphorus pentoxide in toluene to 2-alkyl-5-(4-nitrophenyl)-1,3,4-oxadiazoles, in high yields of 80–90%. The subsequent selective reduction of the nitro group in 2-(4-nitrophenyl)-1,3,4-oxadiazole reactions required the selection of appropriate reagents and conditions. High yields, short reaction times, and easy isolation of products were achieved using the sodium borohydride and hydrated tin(II) chloride reducing system, which was not previously tested in the reduction of this type of 1,3,4-oxadiazole derivative. The synthesis of the titled azo dyes, containing a 5-(4-(phenyldiazenyl)phenyl)-1,3,4-oxadiazole scaffold substituted at position 2 of the heterocyclic core with alkyl groups, was conducted using a typical methodology of diazotization of the previously prepared 4-(5-alkyl-1,3,4-oxadiazol-2-yl)anilines, and then coupling with activated benzene derivatives: phenol, resorcinol and N,N-dimethylaniline. The final products were obtained in high yields (75–93%) and in a relatively short time. The newly synthesized compounds, demonstrating a broad color range spanning orange, red, violet, and even green, and good solubility in some polar solvents, may serve as potential candidates for the dye industry.