4-(Benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine

Abstract

The protocol for the reaction of 2-nitrophenyl azide with 2-(benzo[d]thiazol-2-yl)acetonitrile has been selected. It was found that an optimal condition under which the target 4-(benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine could be formed in good yield is the triethylamine system as a base in the DMF solution. The synthesized triazole is promising both for the evaluation of its antiproliferative properties and for the study of the path to new ring annulation by transforming nitro and amino groups.

1. Introduction

Obtaining arylheterocyclic precursors containing suitably placed ortho functional groups is a convenient tactical technique for creating new polycyclic molecules based on them. For instance, 2-nitroarylheterocyclic compounds with the amino group in the heterocyclic ring in ortho-position to aryl were used for the synthesis of a number of unknown derivatives of quinolino [2,3-c]cinnolines [1], isoxazolo [3,4-c]cinnolinones [2], pyrimido [6,5-i]imidazo [4,5-g]cinnoline [3], quinoxalino [2,3-c]cinnoline [4]. This approach is of interest to us given the possibility of synthesising new polycyclic 1,2,3-triazole derivatives [5] and studying their biological activity [6,7].

It is noteworthy that previously, 1-(2-nitrophenyl)-1H-1,2,3-triazoles were used for the synthesis of new triazolo [1,5-a]quinoxalines [8], 1,2,3-triazolobenzo [1,5]diazepines [9] and 1,2,3-triazolo [1,5-a][1,3,5]benzotriazepine [10]. However, the number of these works is insignificant. This is due to the fact that in the synthesis of 2-nitroaryl triazoles via the base-promoted reaction of ortho-nitro arylazides with active methylene compounds, several side processes occurred [11,12]. Among the side reactions, the competitive Regitz diazotransfer reaction is the most common and is always expected as a side process for cyclocondensation [11]. Therefore, the optimization of synthesis conditions is required for the preparation of 2-nitroaryl triazoles.

This paper describes the preparation and characterization of a new 4-(benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine for the evaluation of its antiproliferative properties and for the study of the methods for its application in the synthesis of new polycyclic 1,2,3-triazole derivatives. 2-(benzo[d]thiazol-2-yl)acetonitrile was chosen as a reagent in the reaction with 2-nitrophenyl azide for the triazole ring formation, because in our previous works [13,14,15], this active methylene nitrile demonstrated high reactivity forming triazoles with yields of 82–97% in a short time with various aromatic azides. Moreover, the benzothiazole motif is widely used in medicinal chemistry for the design of compounds possessing a wide spectrum of biological activities [16].

2. Results and Discussion

It is known that the reaction of azides with methylene active compounds is very sensitive to the base/solvent system [17,18]. Previously, 2-nitrophenyl azide was successfully applied in the synthesis of 2-nitrophenyl-triazoles in the reaction with acetylacetone under Et₃N-DBU catalysis in DMF at room temperature for 12 h [19], acetoacetic anilide under Et₂NH catalysis in DMSO at room temperature for 15 min using ultrasonic irradiation [20], 3-morpholino-3-thioxopropanenitrile under NaOH catalysis in water at 50–60 °C for 3 h [21], ethyl benzoylpyruvate sodium salt in THF at 60 °C for 7 h [8], phenylacetonitrile under Cs₂CO₃ catalysis in DMSO/H₂O at 25 °C for 0.5–2.0 h [22], and 3-(piperidin-1-yl)-3-thioxopropanenitrile under sodium ethoxide catalysis at 0 °C for 1–2 h [23]. Given the above-mentioned results and also the solubility of reagents, a number of conditions were selected, in which the reaction between 2-nitrophenyl azide 1 and 2-(benzo[d]thiazol-2-yl)acetonitrile 2 was studied (Scheme 1, Table 1). All optimization experiments were performed at room temperature (approx. 20 °C), and a load of 1 mmol of azide was used with equimolar amounts of acetonitrile 2 and base. One equivalent of the base was used in all experiments. The previous works showed that the carbon anion generated from the methylene active component was involved in the cyclization [12,13,18]. Obviously, the efficient generation of carbanions requires the equivalent of the base. Control of the reaction was carried out by TLC, identifying the disappearance of the starting azide 1 in the reaction mixture.

We found that the base–solvent system sufficiently affected the yields of 1,2,3-triazole and side product formation. In the MeONa/MeOH system, 1,2,3-triazole 3 started to sediment after the mixing of reagents with an exothermic effect, but the yield was 41%. Tertiary amines such as triethylamine in DMF led to the formation of 1,2,3-triazole 3 with a good yield (78%), but in a long-time period (12 h). 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) significantly increased the reaction rate but led to the formation of large amounts of tarry products. The isolated yield of 1,2,3-triazole 3 was less than 5%. On the contrary, in the system of K₂CO₃/DMSO [18], the reaction occurs with the formation of triazole 3 in moderate yield (67%) after 7 h. Replacement of K₂CO₃ with Cs₂CO₃ significantly accelerated the reaction, but the yield of the target triazole 3 was somewhat lower (53%). In summary, we can conclude that the highest yield of the reaction was in the case of using weaker bases. This is due, in particular, to the fact that when using stronger bases, such as caesium carbonate or sodium methylate, the reaction occurred too quickly with a significant exothermic effect, which led to a significant amount of tarry products. In addition, as the loading of starting reagents increases, it is recommended to pre-cool the reaction mixture or add the starting azide in small portions to control the temperature. Thus, to obtain gram of the target triazole, the protocol with triethylamine was chosen as a base.

In the ¹H-NMR spectrum, the amino group in the triazole is represented by a broad singlet at 7.08 ppm, which is characteristic of aminotriazoles with heterocyclic thiazole and oxadiazole substituents in position 4 [24]. In the ¹³C-NMR spectrum, the formation of triazole is confirmed by a typical carbon in position 5 signal at 145 ppm [24]. Benzothiazole is characterized by weak field signals at 160.3 ppm and 153 ppm corresponding to carbon signals in positions 2 and 3a, respectively (Supplementary Materials).

3. Experimental Section

¹H- and ¹³C-NMR spectra were recorded on Bruker Avance 500 (500 and 126 MHz, respectively) spectrometers in DMSO-d6 solutions using the solvent line as an internal reference. Mass spectral analyses were performed using an Agilent 1100 series LC/MSD with API-ES/APCI mode (200 eV) instrument. Elemental analyses were accomplished using a Carlo Erba 1106 instrument. Melting points were determined on a Boetius melting point apparatus. Progress of reactions and purity of the synthesized compounds were examined by means of TLC on Silufol UV-254 plates, and visualization was performed using UV lamp (254 nm). 2-Nitrophenyl azide 1 [25] and 2-(benzo[d]thiazol-2-yl)acetonitrile 2 [26] were synthesized according to the literature procedures.

Synthesis of 4-(benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine 3. A solution of the 2-nitrophenyl azide 1 (1.64 g, 10.0 mmol) and 2-(benzo[d]thiazol-2-yl)acetonitrile 2 (1.74 g, 10.0 mmol) in DMF (20 mL) was treated by adding Et₃N (1.4 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 12 h. The solution was then diluted with H₂O (20 mL), the precipitate that formed was filtered off, washed with H₂O (10 mL), and dried in a vacuum desiccator over P₄O₁₀. The crude product was purification via crystallization from ethanol–DMF mixture. Yellow solid; yield 78%; m.p. 294–295 °C; ¹H NMR (500 MHz, DMSO-d₆): δ 8.35 (d, J = 7.3 Hz, 1H, H⁷_Bth), 8.11 (d, J = 7.0 Hz, 1H, H⁶_Ar), 8.06–8.00 (m, 1H, H_Arom.), 8.00–7.96 (m, 1H, H_Arom.), 7.95–7.85 (m, J = 7.0 Hz, 2H, H_Arom.), 7.51 (t, J = 6.6 Hz, 1H, H⁵_Bth), 7.40 (t, J = 6.1 Hz, 1H, H⁶_Bth), 7.08 (s, 2H, NH₂). ¹³C NMR (126 MHz, DMSO-d₆): δ 160.3 (C_Bth-2), 153.3 (C_Bth-3a), 145.0 (C_Tr-5), 143.5 (C_Ar-2), 135.1 (CH), 132.4(C_Tr-4), 131.9 (CH), 130.0 (CH), 127.1, 126.4 (CH), 125.9 (CH), 124.6 (CH), 122.3, 122.1 (CH), 121.7 (CH). MS (m/z): 339 (M⁺+1); anal. calcd. for C₁₅H₁₀N₆O₂S: C, 53.25; H, 2.98; N, 24.84; found: C, 53.33; H, 2.90; N, 24.81.

4. Conclusions

The optimal conditions for the reaction of 2-nitrophenyl azide with 2-(benzo[d]thiazol-2-yl)acetonitrile were found, and 4-(benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine was prepared and characterized. Further work will emphasize the evaluation of its antiproliferative properties and investigation of the new synthetic application of nitro and amino groups for a new ring annulation and the preparation of polycyclic derivatives.

Author Contributions

N.T.P. designed the experiments, performed syntheses, obtained the NMR spectra and wrote the draft; M.D.O. analysed the data and finalized the draft. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme and Table

Scheme 1. Synthesis of 4-(benzo[d]thiazol-2-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazol-5-amine 3.

Table 1

Optimization and base solvent effect.

Entry	Base	Solvent	Time, h	Triazole 3 Yield, % [a]
1	MeONa	MeOH	2 [b]	41
2	Et3N	DMF	12	78
3	DBU	DMF	2	5
4	K2CO3	DMSO	7	67
5	Cs2CO3	DMSO	2	53

[a] Isolated yields of a single experiment are given. [b] Sediment started to form after 5 min.

Supplementary Materials

The following are available online, containing NMR spectra of newly synthesized compound 3.

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