Facile synthesis of 3-amino-5-aryl-1,2,4-oxadiazoles via PIDA-mediated intramolecular oxidative cyclization

Abstract

A mild and efficient method for the synthesis of 3-amino-5-aryl-1,2,4-oxadiazole by intramolecular cyclization using PhI(OAc)₂ (PIDA) as an oxidant is developed. Various 3-amino-5-aryl-1,2,4-oxadiazoles are prepared in moderate to good yields, and the PIDA-mediated N–O bond formation mechanism is suggested. In view of the readily available starting materials, operational simplicity, high functionality tolerance, and low toxicity, this protocol provides a novel synthetic strategy for 1,2,4-oxadiazoles.

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Introduction

1,2,4-Oxadiazole derivatives exist in natural products and are widely applied as drugs in pharmaceuticals. They are important five-membered heterocycles with diverse biological activities, such as immunoregulatory,¹ diuretic,² anti-inflammatory³ and anti-diabetic⁴ activities (Fig. 1). Moreover, they are widely used as bioisosteres of other heterocycles to improve activity and stability.⁵

Fig. 1 Structures of some biologically active 1,2,4-oxadiazole derivatives.

Many synthetic methods for synthesizing 3,5-aryl/alkyl-1,2,4-oxadiazoles have been reported.⁶ However, limited knowledge exists on how to synthesize 3-amino-5-aryl-1,2,4-oxadiazoles, which are important privileged structures for drug optimization.⁷ 3-Amino-5-aryl-1,2,4-oxadiazoles are usually prepared from acyl chloride and toxic cyanamide, thereby yielding N-cyanobenzamide, followed by cyclizing with hydroxylamine hydrochloride under a harsh condition,⁸ or cyclizing carboxylic ester with hydroxyguanidine in a low yield.⁹ N. Götz reported a mild method to synthesize N,5-diphenyl-1,2,4-oxadiazol-3-amine using NaOCl as an oxidant with a good yield.¹⁰ Recently, isothiocyanate has been used as a starting material to synthesize 3-amino-5-aryl-1,2,4-oxadiazoles by tandem cyclizing amidinothioureas with hydroxylamine hydrochloride in moderate to high yields.¹¹ Besides, G. C. Tron reported a novel strategy to obtain 1,2,4-oxadiazoles via a multicomponent reaction, followed by Mitsunobu–Beckmann rearrangement.¹² However, most of the above-mentioned methods used unavailable starting materials or toxic agents (cyanamide,^8,10 HgCl₂,^11a CS₂, ^11b which resulted in poor yields. Therefore, developing an effective and environment-friendly method to synthesize 3-amino-5-aryl-1,2,4-oxadiazoles presents a challenge. In this paper, we report an efficient and mild protocol for the synthesis of 3-amino-1,2,4-oxadiazoles in moderate to good yields by cyclizing aromatic N-acylguanidines with PhI(OAc)₂ (PIDA) which is applied in the synthesis of 1,3,4-oxadiazole¹³ (Scheme 1).

Scheme 1 Selected synthetic methods for 3-amino-1,2,4-oxadiazoles.

Results and discussion

Initially, we attempted to establish oxidative cyclization to form an N–O bond, which provided an atom-economic method to synthesize 3-amino-5-aryl-1,2,4-oxadiazoles. When using N-carbamimidoylbenzamide 1a as a model substrate and tert-butyl hydroperoxide (TBHP, 70% aqueous solution) as an oxidant, no desired product was detected when the reaction was performed in 1,2-dichloroethane (DCE) at room temperature when a catalytic amount of CuBr or Cu(OAc)₂ was used under alkaline conditions (Table 1, entries 1–2). Surprisingly, the desired oxadiazole 2a was produced in 46% isolated yield by using PIDA as an oxidant without catalyst and base (Table 1, entry 3). On account of the low solubility in DCE, further screening of the solvents (Table 1, entries 4–6) revealed that dimethylformamide (DMF) served as the most suitable solvent, which obtained 2a in 69% yield (Table 1, entry 6). Inspired by this result, Pd(OAc)₂ and Cu(OAc)₂ was chosen as catalysts respectively, but resulted in decreased yields (Table 1, entries 8–9). Changing the PIDA molar ratio from 1.5 equiv. to 1.3 equiv. reduced the yield of 2a from 69% to 65% (Table 1, entries 6–7). No product formation was observed when using molecular iodine as a catalyst and TBHP or di-tert-butyl peroxide (DTBP) as an oxidant (Table 1, entries 10–11). Therefore, the optimal reaction conditions were as follows: PIDA (1.5 equiv.) as an oxidant in DMF at room temperature for 5 h.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Oxidant (equiv.)	Additive	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.6 mmol, 3 mL of solvent), catalyst (0.12 mmol), oxidant, at room temperature for 5 h.b Isolated yields.c n.d. = not detected.d K2CO3 (1.2 mmol).e K3PO4 (1.8 mmol).f Pd(OAc)2 (0.06 mmol).
1	CuBr	TBHP (2.0)	K2CO3^d	DCE	n.d.^c
2	Cu(OAc)2	TBHP (2.0)	K3PO4^e	DCE	n.d.
3	No one	PIDA (1.5)	No one	DCE	46
4	No one	PIDA (1.5)	No one	CH3CN	39
5	No one	PIDA (1.5)	No one	MeOH	58
6	No one	PIDA (1.5)	No one	DMF	69
7	No one	PIDA (1.3)	No one	DMF	65
8	Pd(OAc)2^f	PIDA (1.5)	No one	DMF	56
9	Cu(OAc)2	PIDA (1.5)	No one	DMF	47
10	I2	TBHP (2.0)	No one	DMF	n.d.
11	I2	DTBP (2.0)	No one	DMF	n.d.

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Having identified the optimal reaction conditions, we then explored the scope and generality of this oxidative annulation reaction. The results are summarized in Table 2. As can be seen, the reactions proceeded smoothly with wide functional group tolerance, the corresponding products were obtained in moderate to good yields (42–79%). The reactivity of the substrates changed with the electronic properties of the substituents on the benzene rings. The presence of electron-withdrawing groups on the phenyl ring, such as the halide, nitro, CF₃, and cyano group, increased the yield (72–79%, except for 2s). The halogen group had a negligible effect on the reaction, thus offering the possibility for further transformation by aromatic substitution or coupling reaction. However, the electron-donating groups, such as methyl- and methoxy-, caused a decrease in the yields (2e, 2i–2k, 2r). The substrates with both electron-withdrawing and electron-donating groups on the phenyl ring reacted well in good yields (2l, 73%; 2m, 75%). The number and positions of the substituents on aromatic rings had an insignificant influence on the conversion. Heteroaromatic structures were also competent to acquire access to the corresponding products in moderate yields (2t, 59%; 2u, 62%). Moreover, N-substituted substances were well tolerated and afforded the corresponding products (2v–2y) in moderate to good yields. When N,N′-dibenzoylguanidine (1v) which can induce convulsion in the brain¹⁴ was used, the corresponding product (2v) could be obtained in 78% yield.

Table 2 Substrate scope for the synthesis of 3-amino-1,2,4-oxadiazoles via oxidative cyclization^a,b

a Reaction conditions: 1 (0.6 mmol), PIDA (0.9 mmol) in DMF at room temperature for 5 h.b Isolated yields.c Room temperature for 6 h.

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In order to explore the reaction mechanism, control experiments were conducted under standard reaction conditions. When radical scavengers, 2,2,6,6-tetramethyl-piperidine-N-oxide (TEMPO) and butylated hydroxytoluene (BHT), were added to the mixture, the reaction proceeded smoothly and was not inhibited, which indicated that this reaction did not proceed via a radical mechanism (Scheme 2).

Scheme 2 Control experiments.

Based on the above results and previous studies,^6a,10 a proposed mechanism is illustrated in Scheme 3. First, the starting material 1a was oxidized in the presence of PIDA to yield N-iodination intermediate 3. Second, intermediate 3 was deprotonated by the base (–OAc) and transformed into intermediate 4a which was identified as a resonance hybrid with intermediate 4b. Finally, intermediate 4a underwent intramolecular cyclization to obtain the desired product 2a. Anion intermediate 4a was stabilized by the electron-withdrawing groups on the phenyl rings, which might explain the relatively high yields of the products.

Scheme 3 Proposed mechanism.

Conclusion

In conclusion, we have developed a novel and efficient synthesis of 3-amino-5-aryl-1,2,4-oxadiazoles via PIDA-mediated oxidative cyclization of available aromatic N-acylguanidines. A proposed mechanism is also established in this study. The reaction is operationally simply, and the conditions are mild and suitable for a wide range of substrates. This method provides a novel synthetic strategy for 1,2,4-oxadiazoles. An investigation on the application of these compounds in medicinal chemistry is currently in progress.

Acknowledgements

This work was supported by the Program for Innovative Research Team of the Ministry of Education and the Program for Liaoning Innovative Research Team in University.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra08871f

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