Phenylselanyl-1H-1,2,3-triazole-4-carbonitriles: synthesis, antioxidant properties and use as precursors to highly functionalized tetrazoles

Abstract

We describe herein our results on the synthesis, antioxidant properties and chemical diversification of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles. These compounds were synthesized in high yields by the reaction of azidophenyl phenylselenides with a range of α-keto nitriles, using DMSO as the solvent in the presence of a catalytic amount of Et₂NH (1 mol%). The synthesized compounds were screened for their in vitro antioxidant activity and 5-phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3a) exhibited the highest antioxidant effect. In addition, the obtained triazoyl carbonitriles were readily transformed into more complex products via a cycloaddition protocol with NaN₃, affording bifunctional hybrids containing triazole and tetrazole systems in good to excellent yields.

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Introduction

Heterocyclic systems have been pointed out as one of the most representative chemical architectures found in several natural and synthetic bioactive compounds.¹ Among them, those containing nitrogen atoms are widely applied in chemical biology.² In particular, 1,2,3-triazoles³ are an interesting class of N-heterocycles broadly used in drug-discovery and modulation of drug candidates.⁴ Several methods for the synthesis of this heterocycle have been already reported via 1,3-dipolar cycloaddition between azides and alkynes under both thermal⁵ and transition metal catalysis based on copper and ruthenium salts.⁶ However, the necessity for transition metals has restricted the application of these methodologies in chemical biology.⁷ For example, copper has been associated with cellular toxicity, metabolic disruption and Cu-induced oxidative damage in biological systems.⁸ To overcome this limitation, organocatalytic approaches involving β-enamine-azide or enolate-azide cycloadditions have been employed to promote the construction of functionalized 1,2,3-triazoles.⁹ Under different reaction conditions, the carbonyl compound could easily generate an enamine or an enolate – both species act as dipolarophiles in organocatalyzed 1,3-dipolar cycloadditions with organic azides.^9a

Recently, our research group described the application of β-enamine-azide cycloadditions for the synthesis of 1,2,3-triazoles bearing organoselenium moieties.¹⁰ A range of selanyl-triazoyl carboxylates and carboxamides were synthesized in good to excellent yields using catalytic amounts of Et₂NH. Organoselenium compounds are valuable molecules in organic synthesis, since these scaffolds are important units in biological sciences¹¹ and also serve as versatile building blocks in organic synthesis.¹² Among them, those containing nitrogen atoms in their structures are a special class of molecules and have been used for several purposes.¹² Selenium-containing 1,2,3-triazole compounds¹³ are an interesting and yet unexplored class of molecules that might have broader biological applications. These hybrid molecules combine the well-known activity of the 1,2,3-triazole ring^3,4 with that of the selenium-containing group.¹² For example, the synthetic 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole (Se-TZ) demonstrated an antidepressant-like effect mediated, at least partially, via the central dopaminergic and serotoninergic neurotransmitter systems.¹⁴

As a continuation of our studies toward the development of new 1,2,3-triazoles bearing organoselenium moieties, we report herein the full results of the synthesis of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles (3). The obtained compounds were screened for their in vitro antioxidant activity. In addition, these compounds were readily transformed into more complex structures by a second cycloaddition with NaN₃, furnishing the desired bifunctional hybrids containing triazole and tetrazole rings (4, Fig. 1).

Fig. 1 General scheme of this work.

Results and discussion

During our studies on the synthesis of arylselanyl-1H-1,2,3-triazole-4-carboxylates starting from azidophenyl arylselenides and β-keto-esters, it was observed that the selanyl-triazoyl carbonitrile (3a) could be efficiently obtained starting from 2-azidophenyl phenylselenide (1a) and using benzoylacetonitrile (2a) instead id β-keto-esters (Scheme 1).^10a The reaction was performed in the presence of 10 mol% of Et₂NH as the catalyst and DMSO as the solvent and, after 18 h at room temperature, the desired product 3a was obtained in 91% yield.

Scheme 1 Previous work.

Owing to our interest in the synthesis of Se-containing triazoles, we decided to perform further control experiments looking for a general method to prepare densely functionalized compounds like 3a. To our delight, we observed that by decreasing the amount of Et₂NH from 10 to 1 mol%, the desired product 3a was obtained in 95% yield after 1 h of reaction at room temperature (Table 1, entry 1). With this result in hand, we focused on extending the scope of this methodology by reacting 2-azidophenyl phenylselenide (1a) with a range of substituted α-keto nitriles under the optimized reaction conditions.

Table 1 Variability in the synthesis of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles^a

Entry	α-Keto nitriles 2a–g	Time (h)	Product (yield)^b
a Reactions were performed with 2-azidophenyl phenylselenide 1a (0.33 mmol) and α-keto nitriles 2a–g (0.3 mmol) using DMSO as the solvent (0.3 mL) at room temperature under air atmosphere and were monitored by TLC until total disappearance of the starting materials.b Yields are given for isolated products.c Reaction performed at 70 °C gave the product 3g in 25% yield.
1		1
2		1
3		1
4		1
5		1.5
6		1
7		24

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The results shown in Table 1 demonstrate that our protocol worked well for a range of substituted α-keto nitriles, affording good yields of the desired products. In general, the reactions were not sensitive to the electronic effect at the aromatic ring in the α-keto nitriles (2). Consequently, α-keto nitriles containing an electron-donating group (4-Me and 4-OMe) and an electron-withdrawing group (4-F, 4-Cl and 4-Br) at the aromatic ring delivered the desired selanyl-triazoyl carbonitriles 3b–f in good yields (Table 1, entries 1–6). Unfortunately, when the reaction was carried out with 4,4-dimethyl-3-oxopentanenitrile (2g), the corresponding product 3g was obtained in low yield, even running the reaction at 70 °C for 24 h (Table 1, entry 7).

We next evaluated the reactivity of 4-azidophenyl phenylselenide (1b) with benzoylacetonitrile (2a) under the same reaction conditions (Scheme 2). In this reaction, however, a mixture of regioisomers (3h and 3h′) was obtained in 90% yield after 2 h [ratio 3h/3h′ (5 : 1)].

Scheme 2 Cycloaddition reaction between 1b and benzoylacetonitrile (2a).

All the synthesized selanyl-triazoyl carbonitriles 3a–h were characterized by their mass, ¹H and ¹³C NMR spectra (see ESI†).

The excessive production of reactive species by cellular respiration and other metabolic activities can cause damage to all cellular structures.¹⁵ Oxidative stress is critical to the etiology of many chronic and degenerative diseases, such as cancer, cardiovascular diseases, diabetes and obesity.¹⁶ In this sense, the search for new synthetic compounds with antioxidant potential has increased in recent years.¹⁷ Aiming to access the possible antioxidant effect of the new selanyl-triazoyl carbonitriles (3), they were subjected to different in vitro assays.

Iron is essential for life in many organisms and for normal neurological function; however, it can participate in redox reactions (electron transfer reactions) with a variety of substrates,¹⁸ which makes it the most important inducer of reactive species in the human organism.¹⁹ Based on this consideration, the ferric ion (Fe³⁺) reducing antioxidant power (FRAP) assay was performed to access the electron donation capability of the synthesized triazoles 3a–e.²⁰ The FRAP of a compound is a valuable indicator of its potential antioxidant activity. It was observed that compound 3a exhibited a high ferric-reducing ability, which increased with its concentration (Table 2). Compounds 3b–e, on the other hand, did not show a significant effect at all the tested concentrations. Based on these data, compound 3a was the best ferric ion reductant.

Table 2 Ferric ion reducing antioxidant power (FRAP) of compound 3a^a

	Absorbance at 593 nm
a Data are presented as the mean ± S.E.M; (**) p < 0.01; (***) p < 0.001 as compared to the respective control sample (FRAP solution without compounds) (one way ANOVA/Newman–Keuls).
Control	0.37 ± 0.08

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Compound 3a (μM)
10	0.44 ± 0.05
50	0.73 ± 0.03**
100	1.03 ± 0.03***

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We also evaluated the capacity of the compounds 3a–e for neutralizing the reactive species (RS) in rat hippocampus (Table 3). The generation of RS can be induced by a variety of oxidants, one of which is azide, which acts by inhibiting the electron transport in Complex IV.²¹

Table 3 Effect of compounds 3a, 3b, 3d, and 3e on the formation of reactive species induced by dichlorofluorescein in rat hippocampus^a

Sample	Fluorescence percentage (%)
a Data are presented as the mean ± S.E.M; (*) p < 0.05; (**) p < 0.01; (***) p < 0.001 compared to dichlorofluorescein sample (3.5 μM) (one way ANOVA/Newman–Keuls).b Control is DMSO.c Imax: maximal inhibition.
Control^b	26.03 ± 0.53
Dichlorofluorescein	100

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Compounds (μM)	3a	3b	3d	3e
10	48.48 ± 25.94**	50.12 ± 21.52*	55.64 ± 15.53	54.04 ± 18.66*
50	24.64 ± 10.54**	29.51 ± 12.97**	22.70 ± 6.26***	42.03 ± 17.54*
100	16.84 ± 4.03**	35.53 ± 14.84**	17.89 ± 7.21***	37.48 ± 20.85*
500	10.63 ± 2.66**	15.58 ± 6.15**	11.58 ± 3.44***	18.12 ± 4.86*
Imax^c (%)	89.37 ± 4.61	84.41 ± 10.66	88.42 ± 5.96	81.95 ± 8.49

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The results from the RS assay suggest that compounds 3a, 3b and 3e decreased the formation of reactive species induced by azide in the hippocampus at concentrations equal to or higher than 10 μM, while 3d was effective only from 50 μM (Table 3). The triazole 3c, containing the methoxyl group, did not show a significant effect. The maximum inhibition (I_max) observed was about 85%, which indicates the high efficacy of compounds 3a–b and 3d–e in this assay.

Compound 3c showed significant activity against RS in the cortex, drastically reducing their activity at the concentration of 500 μM (Table 4). Compounds 3b, 3d and 3e were able to decrease the formation of RS starting at the concentration of 50 μM, while 3a was effective at 10 μM. The I_max of the tested compounds in inhibiting RS in the cortex was around 78%. Based on these outcomes for the RS in the hippocampus and the cortex, it is not possible to infer a clear structure–activity relationship, once all compounds showed a significant ability to protect from the formation of RS. It is possible, in a bigger picture, that this new class of compounds could prevent the oxidative stress.

Table 4 Effect of compounds 3a–e in the formation of reactive oxygen species induced by dichlorofluorescein in rat cortex^a

Sample	Fluorescence percentage (%)
a Data are presented as the mean ± S.E.M; (*) p < 0.05; (**) p < 0.01; (***) p < 0.001 compared to dichlorofluorescein sample (3.5 μM) (one way ANOVA/Newman–Keuls).b Control is DMSO.c Imax: maximal inhibition.
Control^b	9.97 ± 7.38
Dichlorofluorescein	100

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Concentration (μM)/compound	3a	3b	3c	3d	3e
10	59.85 ± 21.52*	69.87 ± 17.92	85.89 ± 7.63	92.03 ± 4.57	64.41 ± 19.60
50	40.12 ± 12.05*	39.82 ± 10.50**	56.44 ± 22.83	49.98 ± 12.36**	40.39 ± 11.98*
100	33.36 ± 11.63*	35.89 ± 16.46**	59.56 ± 13.92	40.39 ± 8.84***	39.85 ± 14.34*
500	24.81 ± 11.34**	12.94 ± 6.40**	23.28 ± 3.28**	27.68 ± 7.29***	20.66 ± 11.08**
Imax^c (%)	75.18 ± 19.63	87.26 ± 10.85	76.72 ± 5.68	72.32 ± 12.63	79.33 ± 19.19

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Compounds 3a–e were evaluated for their capacity to reduce the sodium nitroprusside (SNP)-induced linoleic acid peroxidation. The photodegradation of SNP produces NO, which is a free radical with short half-life (<30 s) and when coupled with other ROS may cause neuronal damage.²² In this assay, all compounds reduced the sodium nitroprusside (SNP)-induced linoleic acid peroxidation (Table 5). Compounds 3a and 3e were effective at a concentration equal or superior to 10 μM, while 3b inhibits the lipid peroxidation from 50 μM. Compounds 3c and 3d showed significant effect only at higher concentrations (500 and 100 μM, respectively). The values of I_max were about 65% in this assay.

Table 5 Effect of compounds 3a–e against sodium nitroprusside induced lipid peroxidation of linoleic acid system^a

Sample	Lipid peroxidation (%)
a Data are presented as the mean ± S.E.M; (*) p < 0.05; (**) p < 0.01 compared to sodium nitroprusside sample (1 mM) (one way ANOVA/Newman–Keuls).b Control is DMSO.c Imax: maximal inhibition.
Control^b	38.43 ± 8.21
Sodium nitroprusside	100

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Concentration (μM)/compound	3a	3b	3c	3d	3e
10	47.84 ± 18.15	74.50 ± 10.92	77.96 ± 12.14	79.03 ± 7.49	71.67 ± 13.08*
50	40.68 ± 17.73*	59.56 ± 14.28*	74.75 ± 8.74	78.56 ± 9.96	58.21 ± 15.86*
100	45.12 ± 6.79*	49.10 ± 14.33*	74.96 ± 10.78	44.36 ± 7.51**	43.26 ± 13.42**
500	35.79 ± 9.42*	46.97 ± 11.86**	56.91 ± 12.26*	46.84 ± 14.22**	48.54 ± 9.48**
Imax^c (%)	69.01 ± 16.81	67.06 ± 13.60	64.53 ± 12.61	65.60 ± 14.96	65.72 ± 11.41

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Due to the ability of compounds 3a–e to protect from the oxidation of linoleic acid, which is a lipid matrix, their potential for inhibiting the lipid peroxidation in the cortex and the hippocampus of rats was evaluated (Tables 6 and 7). It is known that lipid peroxidation in these brain regions is related with neurodegenerative disease, such as Alzheimer disease.²³ The levels of TBARS after lipid peroxidation induced by SNP in the hippocampus were reduced for all compounds at different concentrations. As shown in Table 6, compound 3a was effective starting from a concentration of 50 μM, while 3b showed significant inhibition of the lipid peroxidation at concentrations of 10, 50 and 100 μM. Compounds 3c and 3d were able to protect against lipid peroxidation at 10 μM and 3e was effective only at 500 μM. Therefore, the I_max effect in the hippocampus was in the following order 3a ≥ 3d ≥ 3c ≥ 3b > 3e.

Table 6 Effect of compounds 3a–e on lipid peroxidation induced by sodium nitroprusside in rat hippocampus^a

Sample	Lipid peroxidation (%)
a Data are presented as the mean ± S.E.M; (*) p < 0.05; (**) p < 0.01, compared to sodium nitroprusside sample (100 μM) (one way ANOVA/Newman–Keuls).b Control is DMSO.c Imax: maximal inhibition (%).
Sodium nitroprusside	100

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Concentration (μM)/compound	3a	3b	3c	3d	3e
Control^b	47.17 ± 8.08	53.28 ± 7.90	47.56 ± 7.71	50.20 ± 12.49	46.57 ± 9.22
10	87.13 ± 12.87	61.28 ± 12.48**	46.26 ± 10.49*	54.28 ± 11.31*	80.38 ± 5.18
50	56.90 ± 8.95*	55.42 ± 5.85*	75.28 ± 15.51	70.86 ± 8.29	75.12 ± 6.60
100	63.30 ± 8.37*	56.90 ± 12.88*	61.80 ± 5.87	59.08 ± 14.66	86.21 ± 7.94
500	47.54 ± 9.70**	98.54 ± 8.72	72.14 ± 13.94	91.38 ± 8.62	62.64 ± 10.15*
Imax^c (%)	61.46 ± 5.20	40.00 ± 17.84	50.52 ± 16.16	52.09 ± 19.48	39.55 ± 17.94

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Table 7 Effect of compounds 3a, 3c and 3d on lipid peroxidation induced by sodium nitroprusside in rat cortex^a

Sample	Lipid peroxidation (%)
a Data are presented as the mean ± S.E.M; (*) p < 0.05; (**) p < 0.01, compared to sodium nitroprusside sample (100 μM) (one way ANOVA/Newman–Keuls).b Control is DMSO.c Imax: maximal inhibition (%).
Sodium nitroprusside	100

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Compounds (μM)	3a	3c	3d
Control^b	39.08 ± 4.36	49.77 ± 9.82	47.47 ± 10.79
10	76.50 ± 11.82	62.03 ± 5.49**	60.50 ± 7.65*
50	56.48 ± 22.10*	62.58 ± 4.42**	67.47 ± 7.78*
100	31.67 ± 8.06**	53.61 ± 8.03**	66.98 ± 11.07*
500	16.47 ± 2.43**	78.68 ± 9.07*	72.76 ± 6.86*
Imax^c (%)	83.53 ± 4.21	53.18 ± 9.02	42.63 ± 16.60

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Furthermore, in the cortex, compound 3a was effective starting at the concentration of 50 μM, while compounds 3c and 3d were able to protect against lipid peroxidation at concentrations equal or higher than 10 μM, with an I_max of 3a > 3c ≥ 3d (Table 7). The compound 3a was the most effective in protect the lipid peroxidation among the other in hippocampus and cortex of rats.

In view of the results presented above, compound 3a exhibited a better antioxidant effect when compared to compounds 3b–e, owing to higher value of I_max, and so greater efficacy. It is worth mentioning that this compound has no substituents in their structure leading us to believe that the presence of electron donating groups (–CH₃, –OCH₃) or electron-withdrawing groups (–Cl, –F) substituents does not improve antioxidant activity. Our studies suggest that the presence of nitrile, 1,2,3-triazole ring and arylselenium moieties could contribute to the antioxidant activity of these compounds.

After these antioxidant assays, we returned our attention to verifying the toxicity of compounds 3a–e. To this end, δ-aminolevulinate dehydratase activity (δ-ALA-D) was determined. δ-ALA-D, a sulfhydryl- and zinc-containing enzyme, catalyzes the asymmetrical condensation of two molecules of δ-aminolevulinic acid (δ-ALA) to produce porphobilinogen (PBG) an intermediary in heme biosynthesis.²⁴ δ-ALA-D is a sensitive enzyme inhibited in pro-oxidant situations and by oxidizing agents through oxidation of their sulfhydryl groups.²⁵ Moreover, its activity is an important indicator of organochalcogen toxicity.²⁶ The in vitro results obtained in this study (Tables 8–10) indicate that compounds did not inhibit δ-ALA-D activity, showing the lack of pro-oxidant activity of these compounds, once there is no oxidation of thiol groups to disulfide.

Table 8 Effect of compounds 3a–e on δ-ALA-D activity in the liver of rats^a

Sample	nmol PBG per mg protein
a δ-ALA-D activity is expressed as nmol PBG per mg protein per h. Data are reported as means ± S.D. Data are presented as the mean ± S.E.M; compared to control sample (one way ANOVA/Newman–Keuls).b Control is DMSO.
Control^b	9.77 ± 1.02

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Concentration (μM)/compound	3a	3b	3c	3d	3e
10	9.17 ± 0.71	8.92 ± 0.76	8.38 ± 0.75	10.55 ± 1.18	11.32 ± 1.43
50	9.05 ± 0.64	11.55 ± 0.48	10.06 ± 0.91	9.13 ± 0.28	10.74 ± 1.17
100	11.81 ± 0.57	11.09 ± 0.50	12.02 ± 0.96	11.07 ± 0.39	10.91 ± 0.13
500	10.61 ± 0.30	9.08 ± 0.61	9.13 ± 0.36	10.87 ± 0.40	11.58 ± 0.04

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Table 9 Effect of compounds 3a–e on δ-ALA-D activity in the rat kidney^a

Sample	nmol PBG per mg protein
a δ-ALA-D activity is expressed as nmol PBG per mg protein per h. Data are reported as means ± S.D. Data are presented as the mean ± S.E.M; compared to control sample (one way ANOVA/Newman–Keuls).b Control is DMSO.
Control^b	8.78 ± 0.42

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Concentration (μM)/compound	3a	3b	3c	3d	3e
10	7.06 ± 0.54	8.09 ± 0.62	6.78 ± 0.26	8.65 ± 0.38	7.93 ± 0.17
50	6.68 ± 0.32	6.85 ± 0.55	7.02 ± 0.15	8.53 ± 0.37	7.96 ± 0.26
100	9.00 ± 0.59	7.84 ± 0.08	8.46 ± 0.24	10.28 ± 0.66	9.04 ± 0.50
500	8.65 ± 0.59	6.88 ± 0.52	10.32 ± 0.86	8.93 ± 0.39	9.56 ± 0.38

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Table 10 Effect of compounds 3a–e on δ-ALA-D activity in the rat brain^a

Sample	nmol PBG per mg protein
a δ-ALA-D activity is expressed as nmol PBG per mg protein per h. Data are reported as means ± S.D. Data are presented as the mean ± S.E.M; compared to control sample (one way ANOVA/Newman–Keuls).b Control is DMSO.
Control^b	2.28 ± 0.23

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Concentration (μM)/compound	3a	3b	3c	3d	3e
10	1.93 ± 0.12	2.57 ± 0.13	1.68 ± 0.02	2.01 ± 0.54	2.00 ± 0.10
50	2.44 ± 0.04	2.05 ± 0.12	1.73 ± 0.06	2.24 ± 0.24	2.11 ± 0.20
100	2.26 ± 0.14	1.72 ± 0.08	1.83 ± 0.13	2.21 ± 0.15	1.86 ± 0.19
500	2.86 ± 0.15	1.94 ± 0.12	1.85 ± 0.04	2.35 ± 0.13	1.91 ± 0.22

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The selanyl-triazoyl carbonitriles (3) appear highly promising as intermediates for the preparation of more complex structures, such as tetrazoles. Tetrazoles have shown valuable properties in a wide range of applications, such as in material sciences,²⁷ as propellants and explosives,²⁸ catalysis,²⁹ etc.³⁰ Tetrazole derivatives are well known compounds with a high level of biological activity³¹ and are used in pharmaceuticals as carboxylic acids isosteres.³² An advantage of tetrazole derivatives over carboxylic acids is that they are resistant to various biological metabolic degradation pathways, conferring to the corresponding drug a longer bioavailability.³² Therefore, there is considerable interest in the development of efficient synthesis of highly functionalized and complex 1H-tetrazoles. In this regard, the most attractive way for their synthesis is the [2 + 3] cycloaddition involving nitriles and azides.³³

A few years ago, our group developed the synthesis of selanyl substituted 1H-tetrazoles by treatment of arylselanyl–alkylnitriles with NaN₃ in the presence of zinc bromide in aqueous solution.³⁴ Attempts to extend the previously described conditions to the reaction between selanyl-triazoyl carbonitrile 3a and NaN₃ to prepare the respective selanyl-triazoyl tetrazole 4a failed completely; even after 48 h under reflux (Scheme 3).

Scheme 3 First attempt to obtain selanyl-triazoyl tetrazole 4a.

Nasrollahzadeh and co-workers described in 2002 the preparation of 5-substituted 1H-tetrazoles using FeCl₃–SiO₂ as a heterogeneous catalyst.³⁵ Because of the complexity of our starting nitrile, we decide to adapt this procedure; however, we used Al₂O₃ as a solid support instead of SiO₂. Thus, the reaction of selanyl-triazoyl carbonitrile 3a with NaN₃ using FeCl₃–Al₂O₃ as the catalyst in DMF at 120 °C for 48 hours under air atmosphere furnished the desired product 4a in 63% yield (Table 11, entry 1). Considering this a satisfactory result, we turned our attention to the evaluation of a range of other selanyl-triazoyl carbonitriles (3; Table 11).

Table 11 Diversity in the synthesis of selanyl-triazoyl tetrazoles^a

Entry	Product (yield)^b	Entry	Product (yield)^b
a Reactions were performed with phenylselanyl-1H-1,2,3-triazole-4-carbonitriles 3a–f (0.3 mmol), NaN3 (0.45 mmol), Al2O3/FeCl3 as the catalyst (0.018 g), DMF as the solvent (1.5 mL) at 120 °C for 48 h under air atmosphere.b Yields are given for isolated products.
1		4
2		5
3		6

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The results shown in Table 11 demonstrate that selanyl-triazoyl carbonitriles 3b–f were efficiently converted to the respective tetrazole derivatives 4b–f. Therefore, selanyl-triazoyl carbonitriles containing EDG and EWG on the aromatic ring gave good yields of the desired selanyl-triazoyl tetrazoles 4b–f (Table 11, entries 2–6). All the spectral data (MS and NMR analysis) supported and confirmed the formation of the target compounds 4.

Conclusions

In conclusion, we demonstrated our results on the synthesis, antioxidant properties and synthetic application of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles. This new class of compounds was synthesized in high yields by the reaction of azidophenyl phenylselenides with a range of α-keto nitriles in the presence of a catalytic amount of Et₂NH. Five of the synthesized compounds were screened for their in vitro antioxidant activity and the results demonstrated that selanyl-triazoyl carbonitrile 3a is a better antioxidant than the other synthesized compounds. The selanyl-triazoyl carbonitriles were readily manipulated to yield the desired bifunctional hybrid selanyl-triazoyl tetrazoles in good yield by reaction with NaN₃ in Al₂O₃/FeCl₃ as a catalytic system. These synthetic methods proved to be efficient for the synthesis of new selenium-containing nitrogen heterocycles. Other bioassays are currently in progress to verify other possible activities of the selanyl-triazoyl carbonitriles derivatives as well as the mechanism involved.

Experimental section

General remarks

Proton nuclear magnetic resonance spectra (¹H NMR) were obtained at 400 MHz on a Bruker DPX-400 NMR spectrometer. Spectra were recorded in CDCl₃. Chemical shifts are reported in ppm, with tetramethylsilane (TMS) used as the external reference. Data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz and integrated intensity. Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 100 MHz on a Bruker DPX-400 NMR spectrometer. Spectra were recorded in CDCl₃. Chemical shifts are reported in ppm in reference to the solvent peak of CDCl₃. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), t (triplet), dt (doublet of triplet) and m (multiplet). Mass spectra (MS) were measured on a Shimadzu GCMS-QP2010 mass spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker Micro TOF-QII spectrometer 10416. Column chromatography was performed using a Merck Silica Gel (230–400 mesh). Thin layer chromatography (TLC) was performed using a 0.25 mm thick Merck Silica Gel GF₂₅₄. For visualization, TLC plates were either placed under ultraviolet light or stained with iodine vapor or acidic vanillin.

General procedure for the synthesis of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles 3a–h

The appropriate α-keto nitrile (out of 2a–g, 0.3 mmol) was first added to a solution of the appropriate azidophenyl phenylselenide (out of 1a–b, 0.33 mmol) in DMSO (0.3 mL), followed by diethylamine (0.003 mmol) as the catalyst. The reaction mixture was stirred in an open vial for the time indicated in Table 1 and Scheme 2. After completion of the reaction, the crude product was purified by column chromatography on silica gel with a mixture of hexane/ethyl acetate (5 : 1) as the eluent to afford the desired product (3a–h). Spectral data for the products prepared are listed below.

5-Phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3a). Yield: 0.091 g (91%); yellow solid; m.p. 94–96 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.49–7.23 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz) δ = 144.11, 135.15, 134.79, 133.85, 132.43, 131.50, 130.97, 129.65, 129.23, 128.75, 128.70, 128.24, 128.07, 123.22, 119.69, 112.21. MS (relative intensity) m/z: 403 (6), 402 (22), 400 (12), 297 (48), 294 (100), 293 (40), 217 (53), 190 (60), 77 (41), 51 (26). HRMS: calculated to C₂₁H₁₅N₄Se [M + H]⁺: 403.0462. Found 403.0470.

1-(2-(Phenylselanyl)phenyl)-5-(p-tolyl)-1H-1,2,3-triazole-4-carbonitrile (3b). Yield: 0.112 g (80%); orange solid; m.p. 88–90 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.36–7.16 (m, 13H), 2.34 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ = 144.26, 141.50, 135.34, 134.73, 133.92, 132.38, 131.42, 129.94, 129.60, 128.67, 128.55, 128.20, 128.08 (2C), 120.23, 119.41, 112.36, 21.43. MS (relative intensity) m/z: 417 (13), 416 (48), 414 (26), 387 (23), 311 (63), 309 (59), 308 (100), 298 (13), 296 (64), 294 (35), 293 (23), 232 (38), 231 (77), 216 (21), 204 (30), 179 (21), 153 (17), 152 (78), 151 (18), 77 (52), 51 (29). HRMS calcd for C₂₂H₁₇N₄Se [M + H]⁺: 417.0618. Found: 417.0596.

5-(4-Methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3c). Yield: 0.102 g (79%); yellow solid; m.p. 115–117 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.38–7.24 (m, 11H), 6.89 (dt, J = 8.9 and 2.9 Hz, 2H), 3.82 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ = 161.51, 144.05, 135.35, 134.76, 133.87, 132.40, 131.40, 130.20, 129.60, 128.68, 128.14, 128.09, 128.06, 119.01, 115.16, 114.74, 112.51, 55.37. MS (relative intensity) m/z: 433 (14), 432 (54), 430 (27), 329 (17), 327 (85), 325 (51), 324 (49), 323 (20), 312 (21), 309 (23), 296 (53), 294 (28), 248 (20), 247 (100), 232 (28), 204 (15), 152 (55), 151 (14), 77 (28), 51 (17), 43 (13). HRMS calcd for C₂₂H₁₇N₄OSe [M + H]⁺: 433.0568. Found: 433.0545.

5-(4-Fluorophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3d). Yield: 0.106 g (84%); orange solid; m.p. 119–121 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.36–7.24 (m, 11H), 7.06 (t, J = 8.4 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ = 163.80 (d, J = 253 Hz), 134.97, 134.27, 133.93 (2C), 131.92, 131.53, 130.80 (d, J = 8.9 Hz), 129.52, 128.57, 128.21, 128.01, 127.82, 119.46, 119.24 (d, J = 3.5 Hz), 116.45 (d, J = 22.3 Hz), 111.91. MS (relative intensity) m/z: 421 (9), 420 (39), 418 (19), 391 (18), 389 (12), 315 (65), 314 (32), 313 (49), 312 (100), 311 (39), 235 (60), 232 (17), 208 (40), 183 (12), 179 (13), 153 (11), 152 (50), 77 (30), 51 (19). HRMS calcd for C₂₁H₁₄FN₄Se [M + H]⁺: 421.0368. Found: 421.0338.

5-(4-Chlorophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3e). Yield: 0.107 g (82%); yellow solid; m.p. 99–100 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.42–7.26 (m, 13H). ¹³C NMR (CDCl₃, 100 MHz) δ = 143.09, 137.49, 135.03, 134.50, 134.13, 132.18, 131.72, 129.93, 129.72, 129.66, 128.78, 128.32, 128.09, 127.89, 121.67, 119.76, 111.97. MS (relative intensity) m/z: 438 (23), 436 (47), 434 (25), 408 (15), 407 (24), 333 (23), 331 (56), 330 (39), 329 (52), 328 (100), 327 (23), 296 (89), 294 (52), 292 (37), 251 (60), 232 (26), 224 (25), 216 (33), 190 (24), 179 (23), 157 (12), 152 (85), 77 (54), 76 (12), 51 (34). HRMS calcd for C₂₁H₁₄ClN₄Se [M + H]⁺: 437.0072. Found: 437.0071.

5-(4-Bromophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3f). Yield: 0.108 g (75%); yellow solid; m.p. 105–106 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.53 (dt, J = 8.8 and 2.6 Hz, 2H), 7.41–7.31 (m, 5H), 7.27–7.24 (m, 4H), 7.22 (dt, J = 8.8 and 2.6 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ = 143.14, 135.03, 134.47, 134.18, 132.62, 132.15, 131.73, 130.07, 129.73, 128.78, 128.34, 128.09, 127.90, 125.85, 122.14, 119.73, 111.95. MS (relative intensity) m/z: 482 (84), 481 (13), 480 (43), 478 (20), 451 (20), 377 (32), 375 (53), 374 (66), 373 (44), 372 (68), 298 (25), 297 (51), 296 (100), 295 (48), 294 (53), 293 (43), 268 (16), 232 (25), 216 (36), 190 (27), 179 (21), 152 (74), 115 (10), 114 (16), 77 (49), 51 (31). HRMS calcd for C₂₁H₁₄BrN₄Se [M + H]⁺: 480.9567. Found: 480.9583.

5-(tert-Butyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3g). Yield: 0.025 g (22%); yellow solid; m.p. 94–95 °C. ¹H NMR (CDCl₃, 400 MHz) δ = 7.55–7.53 (m, 2H), 7.43–7.32 (m, 6H), 7.26–7.22 (m, 1H), 1.42 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz) δ = 152.32, 136.25, 135.57, 134.75, 132.18, 131.60, 129.87, 129.15, 128.76, 128.60, 127.06, 119.10, 113.26, 32.55, 30.05. MS (relative intensity) m/z: 382 (31), 380 (16), 339 (29), 298 (24), 297 (31), 295 (19), 277 (23), 273 (10), 271 (12), 259 (16), 232 (21), 219 (15), 218 (64), 197 (21), 190 (11), 182 (26), 157 (26), 155 (26), 152 (41), 115 (11), 77 (43), 57 (100), 51 (25), 41 (50). HRMS calcd for C₁₉H₁₉N₄Se [M + H]⁺: 383.0775. Found: 383.0746.

5-Phenyl-1-(4-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (3h). Yield: 0.108 g (90%); yellow oil; ¹H NMR (CDCl₃, 400 MHz) δ = 7.59–7.56 (m, 2H), 7.50–7.33 (m, 10H), 7.18 (d, J = 8.0 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ = 142.85, 136.13, 134.87, 133.49, 131.64, 131.09, 129.74, 129.41, 128.84, 128.67, 128.32, 125.50, 123.15, 120.56, 111.92. MS (relative intensity) m/z: 402 (14), 400 (7), 374 (28), 371 (6), 295 (25), 294 (100), 293 (14), 232 (21), 230 (11), 218 (12), 217 (62), 216 (12), 190 (34), 179 (10), 165 (8), 157 (15), 153 (10), 152 (27), 115 (23), 114 (12), 77 (27), 51 (16). HRMS calcd for C₂₁H₁₅N₄Se [M + H]⁺: 403.0462. Found: 403.0447.

General procedure for the synthesis of 5-aryl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl-1H-tetrazoles 4a–f

A mixture of the appropriate phenylselanyl-1H-1,2,3-triazole-4-carbonitrile (out of 3a–f, 0.3 mmol), sodium azide (0.5 mmol), Al₂O₃/FeCl₃ (0.018 g) and DMF (1.5 mL) was taken in a round-bottomed flask and stirred at 120 °C for 48 h under air atmosphere. After this time, HCl (3 M, 2 mL) and ethyl acetate (10 mL) were added, and vigorous stirring was continued until no solid was present and the aqueous layer had a pH of 2. The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried with MgSO₄ and evaporated under reduced pressure. The resultant products were isolated in a chromatography column with hexane/ethyl acetate as the eluent and recrystallized if necessary to afford the desired product (4a–f). Spectral data for the products prepared are listed below.

5-(5-Phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4a). Yield: 0.084 g (63%); white solid; m.p. 241–242 °C; ¹H NMR (CDCl₃, 400 MHz) δ = 7.48–7.26 (m, 15H). ¹³C NMR (CDCl₃, 100 MHz) δ = 138.13, 135.19, 134.30, 132.92, 132.16, 131.16, 130.66, 129.96, 129.62, 129.23, 128.20, 128.07, 127.95, 127.84, 127.32, 124.22. MS (relative intensity) m/z: 446 (9), 445 (36), 443 (20), 402 (16), 360 (15), 340 (21), 297 (36), 294 (61), 293 (26), 281 (32), 280 (28), 271 (66), 269 (38), 232 (49), 217 (29), 205 (34), 190 (35), 179 (17), 152 (78), 151 (27), 139 (16), 129 (32), 111 (21), 103 (25), 97 (38), 77 (81), 69 (60), 63 (15), 60 (20), 57 (76), 51 (42), 44 (52), 43 (95), 41 (54), 40 (100). HRMS calcd for C₂₁H₁₆N₇Se [M + H]⁺: 446.0632. Found: 446.0621.

5-(1-(2-(Phenylselanyl)phenyl)-5-(p-tolyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4b). Yield: 0.095 g (75%); yellow solid; m.p. 149–151 °C; ¹H NMR (CDCl₃, 400 MHz) δ = 7.38–7.23 (m, 12H), 7.15 (d, J = 8 Hz, 2H), 2.34 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ = 148.26, 140.72, 139.37, 135.74, 134.75, 133.74, 132.68, 131.15, 130.73, 130.31, 129.61, 129.30, 128.69, 128.58, 128.32, 127.80, 121.08, 21.44. MS (relative intensity) m/z: 461 (15), 460 (19), 459 (72), 457 (38), 416 (20), 374 (20), 354 (26), 326 (22), 308 (52), 285 (100), 283 (59), 246 (29), 232 (45), 231 (74), 217 (31), 204 (26), 152 (72), 143 (29), 117 (27), 91 (28), 78 (23), 77 (66), 57 (21), 55 (20), 51 (35), 44 (18), 43 (28), 40 (35). HRMS calcd for C₂₂H₁₈N₇Se [M + H]⁺: 460.0789. Found: 460.0747.

5-(5-(4-Methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4c). Yield: 0.081 g (57%); white solid; m.p. 193–195 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ = 7.68–7.66 (m, 1H), 7.46–7.44 (m, 2H), 7.39–7.35 (m, 7H), 7.28–7.26 (m, 1H), 6.96 (d, J = 8.5 Hz, 2H), 3.77 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ = 160.34, 148.22, 138.32, 135.47, 134.12, 133.06, 131.67, 131.56, 131.40, 130.61, 129.78, 128.95, 128.58, 128.28, 128.22, 116.10, 113.78, 55.16. MS (relative intensity) m/z: 475 (2), 368 (11), 298 (8), 232 (8), 152 (17), 133 (14), 129 (14), 121 (13), 111 (21), 98 (27), 97 (37), 83 (50), 77 (17), 71 (44), 69 (54), 57 (100), 56 (24), 55 (92), 44 (33), 43 (86), 42 (15), 41 (51), 40 (31). HRMS calcd for C₂₂H₁₈N₇OSe [M + H]⁺: 476.0738. Found: 476.0700.

5-(5-(4-Fluorophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4d). Yield: 0.078 g (56%); brown solid m.p. 92–94 °C; ¹H NMR (CDCl₃, 400 MHz) δ = 7.52–7.48 (m, 2H), 7.34–7.27 (m, 9H), 7.05 (t, J = 8.7 Hz, 2H). ¹³C NMR (CDCl₃, 100 MHz) δ = 163.72 (d, J = 252 Hz), 148.07, 138.30, 134.64, 133.61, 132.64, (d, J = 8.7 Hz), 132.02, 131.42, 130.93, 129.70, 128.72, 128.30, 128.15, 127.92, 120.03 (d, J = 2.6 Hz), 119.16, 115.88 (d, J = 22.0 Hz). MS (relative intensity) m/z: 383 (2), 355 (3), 155 (14), 137 (8), 127 (15), 125 (10), 111 (20), 98 (22), 97 (38), 85 (32), 84 (25), 77 (7), 73 (18), 71 (51), 67 (23), 57 (100), 56 (26), 55 (83), 44 (44), 43 (98), 41 (45), 40 (14). HRMS calcd for C₂₁H₁₅FN₇Se [M + H]⁺: 464.0538. Found: 464.0529.

5-(5-(4-Chlorophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4e). Yield: 0.139 g (96%); white solid; m.p. 238–240 °C; ¹H NMR (CDCl₃, 400 MHz) δ = 7.46 (d, J = 8.5 Hz, 2H), 7.36–7.27 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz) δ = 147.88, 138.17, 136.91, 135.22, 134.55, 133.83, 132.47, 131.78, 131.52, 130.80, 129.74, 128.96, 128.73, 128.27, 128.20, 128.03, 122.41. MS (relative intensity) m/z: 479 (2), 367 (11), 339 (6), 313 (9), 239 (9), 171 (8), 152 (6), 137 (9), 135 (9), 129 (13), 123 (14), 121 (10), 111 (21), 110 (10), 109 (19), 98 (30), 97 (41), 95 (36), 85 (32), 71 (43), 70 (15), 69 (56), 57 (98), 55 (100), 44 (11), 43 (73), 42 (10), 41 (46). HRMS calcd for C₂₁H₁₅ClN₇Se [M + H]⁺: 480.0243. Found: 480.0353.

5-(5-(4-Bromophenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)-1H-tetrazole (4f). Yield: 0.094 g (59%); white solid; m.p. 216–217 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ = 7.18–7.16 (m, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.94–6.89 (m, 2H), 6.88–6.72 (m, 9H). ¹³C NMR (DMSO-d₆, 100 MHz) δ = 148.38, 137.32, 135.11, 133.99, 133.17, 132.21, 131.79, 131.37, 131.20 (2C), 129.80, 129.04, 128.60, 128.40, 128.06, 123.88, 123.72. MS (relative intensity) m/z: 525 (19), 523 (24), 480 (17), 374 (32), 372 (34), 349 (22), 311 (23), 296 (50), 295 (23), 231 (53), 190 (27), 157 (22), 152 (87), 97 (35), 89 (21), 71 (39), 69 (55), 57 (88), 55 (99), 50 (32), 43 (100), 42 (21), 41 (64), 40 (73). HRMS calcd for C₂₁H₁₅BrN₇Se [M + H]⁺: 523.9738. Found: 523.9727.

Acknowledgements

We are grateful to CAPES, CNPq (Grants 306430/2013-4, 400150/2014-0 and 447595/2014-8), FAPESP (15/17141-1 and 14/50249-8), FINEP and FAPERGS for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra22445d

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