Synthesis of highly diversified 1,2,3-triazole derivatives via domino [3 + 2] azide cycloaddition and denitration reaction sequence

Abstract

In this paper, an elegant synthesis of 1,2,3-triazole derivatives via domino [3 + 2] azide cycloaddition and denitration reaction sequence under catalyst free conditions has been described. Treatment of Baylis–Hillman adducts and their cyclic derivatives from nitroolefins with sodium azide in the absence of catalyst smoothly afforded the 1,2,3-triazole derivatives in excellent yields.

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Introduction

Triazoles are important molecular entities due to their unique chemical as well as physical properties.¹ They are well known for a wide range of applications in organic, organometallic, medicinal, and material chemistry sectors.² 1,2,3-Triazoles are found to be versatile building blocks in organic synthesis and can exhibit vital importance in pharmacological applications owing to their stability towards light, moisture and oxygen.^3–5 This framework belongs to an expedient class of pharmacophores since it shows a significant resistance to metabolic transformations such as oxidation, reduction, basic or acidic hydrolysis. The 1,2,3-triazole unit is present in numerous bio-active entities exhibiting interesting properties such as antibacterial, anti-HIV, antiallergic, antiparasitic, anti-fungal, anti-viral and anti-microbial activities.^6–10 In recent times, 1,2,3-triazoles have been exploited as a backbone of a bidentate phosphine ligand and also find an array of applications in the industrial sector as photosensitizers, dyes, agrochemicals and are commercially utilized as anti-corrosive agents.¹¹ Some of the representative examples of biologically active molecules containing 1,2,3-triazoles¹² (I–IV) are shown in Fig. 1.

Fig. 1 Some of the triazole containing bio-active molecules.

1,2,3-Triazoles have been receiving emerging prominence regarding their versatile applications¹³ and consequently significant advances have been made in accessing such frame works with diverse functionalities which represents one of the ongoing program in modern organic synthesis.

Reported procedures¹⁴ involves click chemistry concept utilizing acetylenic systems with azide to produce 1,2,3-triazole via 1,3-dipolar cycloaddition reaction under the influence of metal catalysts along with additives or catalysts. Therefore, the development of highly efficient protocols for accessing such molecular entities in an effective manner through simplified reaction condition with wide substrate scope is highly desirable.

In literature, variety of reports are available for the synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition reaction on β-nitrostyrenes.^14k–m For instance, Guan and co-workers reported the synthesis of 4-aryl-NH-1,2,3-triazoles in moderate to good yields from 1,3-dipolar cycloaddition of nitroolefins with NaN₃ using p-toluenesulfonic acid (0.5 equiv.).^14j Similarly, Pan and co-workers developed a method for the preparation of 1,5-disubstituted 1,2,3-triazoles via Ce(OTf)₃ catalyzed [3 + 2] cycloaddition of azides with nitroolefins.^14l Even though these procedures are attractive, they found to have certain limitations such as limited substrate scope, utilization of catalyst, long reaction time for reaction completion, moderate yields which invoke the development of a new and efficient protocol to construct highly diversified 1,2,3-triazoles in an elegant manner. In literature, we could not find any report for the cycloaddition reaction of the Baylis–Hillman¹⁵ adducts and its cyclic derivatives derived from nitroolefins towards the synthesis of 1,2,3-triazoles. Therefore, we envisaged that, the 1,2,3 triazole crafted new Baylis–Hillman derivatives¹⁶ may have variety of bioactivities since the 1,2,3-triazole derivatives are already known for various biological activities. With this striking idea we have decided to begin a new program for the synthesis of library of 1,2,3-triazoles by utilizing the Baylis–Hillman adducts derived from nitroolefins.¹⁷

Usually, click chemistry for triazole formation are achieved by employing alkynes and azide. However, it occurs to us that the synthesis of substituted 1,2,3-triazole can be achieved using sodium azide and Baylis–Hillman adduct derived from nitroolefin via tandem 1,3-dipolar cycloaddition followed by denitration reaction sequence. To achieve our goal, we investigated the reaction between (E)-2-nitro-3-phenylprop-2-en-1-ol (1a) and sodium azide (2) under various reaction conditions. The best result was obtained when we carried out the reaction at 80 °C for 10 minutes, the reaction was almost completed and successfully led to the desired substituted 1,2,3-triazole derivative in 87% yield according to Scheme 1.

Scheme 1

It is important to mention here that this is the first report for the synthesis of 1,2,3-triazole derivative from Baylis–Hillman adduct derived from nitroolefins through tandem 1,3-dipolar cycloaddition followed by denitration reaction sequence under catalyst free condition. The reaction was carried out without an exclusion of air and moisture to obtain the product in excellent yield, which demonstrates the efficiency of this protocol.

Encouraged by this result, we treated various B. H adducts (1b–j) with 2 equiv. sodium azide (2) without any catalyst in DMSO solvent at 80 °C, successfully led to the desired five membered triazole compounds. i.e. (5-aryl-1H-1,2,3-triazol-4-yl)methanols (3b–j) in excellent yields (80–92%) as shown in Table 1. It is worth mention here that in the process of product formation, the nitro group got eliminated. The results are summarized in Table 1.

Scheme 2

Table 1 Synthesis of 1,2,3-triazoles (3a–j) using Baylis–Hillman adducts (1a–j)

Entry	Substrate	Product^a	Yield^b (%)
a All reactions were carried out using 1 mmol of Baylis–Hillman alcohol (1a–j) with 2 mmol of NaN3 in 5 mL of DMSO at 80 °C.b Yields of the pure products (3a–j) obtained after column chromatography (silica gel, 20% EtOAc in hexanes).
1			87
2			91
3			82
4			92
5			80
6			92
7			80
8			81
9			83
10			85

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To further understand the generality of the reaction and its applicability to the Friedel–Crafts derivatives synthesized from Baylis–Hillman adducts, we treated (E)-2-nitro-3-aryl, 1-phenylprop-1-enes (4, 5 and 6) with 2 equiv. sodium azide without any catalyst in DMSO solvent at 80 °C for 10 minutes, successfully led to the desired 4-aryl-1H-1,2,3-triazoles (7, 8 and 9) in excellent yields (81–84%) as shown in the Scheme 2.

The plausible mechanism for the formation of 1,2,3-triazole involving tandem (3 + 2) cycloaddition followed by denitration sequence is shown below (Scheme 3).

Scheme 3

Further to investigate the mechanistic aspects of this azide cycloaddition reaction, we carried out the reaction at different temperature levels (from −5 °C to 0 °C, rt and 80 °C) to isolate the intermediate from the reaction. Under these conditions, we observed only starting material as well as product and we didn't observe any isolable intermediate, even at −5 °C as shown below (Scheme 4).

Scheme 4

From the above experiments, we conclude that there is no stable as well as isolable intermediate was observed during the cycloaddition reaction. Based on the literature^14l report, we would like to mention here that the reaction proceeds via [3 + 2] cycloaddition and denitration reaction sequence as shown in Scheme 3.

Further to extend the scope of the reaction, we treated 2-benzoxepine (10a) with 2 equiv. sodium azide without any catalyst in DMSO solvent at 80 °C for 30 minutes successfully led to the desired fused tricyclic six, seven and five membered benzoxepine fused triazole (11a) in 96% yield (Scheme 5).

Scheme 5

Encouraged by this result, we treated a variety of 2-benzoxepines (10b–j) derived from the Baylis–Hillman adducts with 2 equiv. sodium azide in DMSO solvent at 80 °C for 30 minutes successfully led to the desired tricyclic benzoxepine fused triazole products (11b–j) in 81–96% yields (Scheme 5). The results are summarized in Table 2.

Table 2 Synthesis of benzoxepine fused 1,2,3-triazoles (11a–j) using Baylis–Hillman derivatives (10a–j)

Entry	Substrate	Product^a	Yield^b (%)
a All reactions were carried out using 1 mmol of benzoxepine (10) with NaN3 (2 mmol) in 5 mL of DMSO at 80 °C.b Yields of the pure products (11) obtained after column chromatography (silica gel, 20% EtOAc in hexanes).
1			96
2			90
3			94
4			96
5			96
6			82
7			81
8			82
9			86
10			92

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We also explored the additional scope of the reaction by the treatment of 2-bromostyrene (12)/2-iodo styrene (13)/cinnamic acid (14) with sodium azide under similar reaction conditions, however no product formation was observed under this catalyst free condition even up to 3 hours (Scheme 6). These substrates undergo azide cycloaddition only in the presence of metal catalysts as reported in the literature.¹⁸

Scheme 6

To probe further the generality of the reaction, we have also treated dinitroderivative (15) (E)-(2,3-dinitroprop-1-en-1-yl)benzene with sodium azide in DMSO solvent at 80 °C which successfully afforded the desired product in 81% yield (Scheme 7).

Scheme 7

Conclusions

The development of new protocol for the efficient synthesis of novel class of 1,2,3-triazole compound from Baylis–Hillman adducts derived from nitroolefins via tandem dipolar cyclo addition followed by denitration reaction sequence has been achieved successfully. 1,3-Diaryl nitroolefins also conveniently transformed into corresponding 1,2,3-triazole derivatives efficiently. Furthermore, 4-nitro-1,3-dihydrobenzo[c]oxepines also smoothly led to the interesting class of tricyclic benzoxepino 1,2,3-triazoles in excellent yields. Since 1,2,3-triazoles and its derivatives are well screened for their interesting biological properties, the newly synthesized compounds may also exhibit similar kind of medicinal properties.

Acknowledgements

We thank DST-SERB, New Delhi for the financial support. We also thank DST-FIST for the NMR facility. A. D thank CSIR for SRF and P. V. K thank UGC for JRF.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Representative experimental procedures, with all spectral data of 3a–j, 5, 7, 9, 11a–j and 16. See DOI: 10.1039/c5ra14195h

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