Metal-free construction of diverse 1,2,4-triazolo[1,5-<i>a</i>]pyridines on water

Citation: Chunhua Ma, Mengjiao Liu, Siyu Ouyang, Zhenwei Cui, Jingjing Bi, Yuqin Jiang, Zhiguo Zhang. Metal-free construction of diverse 1,2,4-triazolo[1,5-a]pyridines on water[J]. Chinese Chemical Letters, 2025, 36(1): 109755. doi: 10.1016/j.cclet.2024.109755 shu

Metal-free construction of diverse 1,2,4-triazolo[1,5-a]pyridines on water

English

Metal-free construction of diverse 1,2,4-triazolo[1,5-a]pyridines on water

a.
Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
b.
Chongqing Aoshe Bio-chemical Co. Ltd., Chongqing 400000, China
^* Corresponding authors.
E-mail addresses: 2016007@htu.edu.cn (C. Ma)
jiangyuqin@htu.edu.cn (Y. Jiang)
zhangzg@htu.edu.cn (Z. Zhang).
Received Date: 21 December 2023
Accepted Date: 05 March 2024
Revised Date: 23 February 2024
Available Online: 15 January 2025

Abstract: A transition-metal- and oxidant-free amination/cyclization reaction to access 1,2,4-triazolo[1,5-a]pyridines was realized in water by using amino diphenylphosphinate as amino source. A broad array of readily accessible N-(pyridyl)amides could be converted into the products featuring a diverse set of functional groups. The sustainable methodology was successfully applied to the late-stage functionalization of natural products and drugs.

Key words:

Sustainable synthetic practices, especially green solvents, transition-metal free, and strong oxidants-free strategies, are highly desired to medicinal chemistry and synthetic chemistry [1-4]. The sustainable construction of nitrogen-containing compounds is an enduring topic, owing to their value in drugs, bioactive compounds and functional materials [5-8]. As one of the most important triazole heterocycles, 1,2,4-trizaolo[1,5-α]pyridines are widely found in drug candidates and natural products (Fig. 1), such as glucose-lowering drug candidate LY3104607 [9], cancer immunotherapeutic/antifibrotic agent EW-7197 [10], anti-atopic dermatitis agent LEO 39652 [11], and prolylhydroxylase domain enzayme PHD-1 inhibitor Takeda-39 [12]. Hence, the construction of 1,2,4-trizaolo[1,5-α]pyridines in a sustainable fashion is highly desirable.

Figure 1

Figure 1. The bioactive molecules bearing the 1,2,4-trizaolo[1,5-α]pyridines fragment.

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Several strategies have been developed to access this important heterocyclic moiety. In 2009, Nagasawa’s group reported a CuBr catalyzed oxidative coupling approach of nitrile with 2-aminopyridine to yield the 1,2,4-triazoles in 1,2-dichlorobenzene DCB (Scheme 1a) [13]. Afterwards, this catalytic system was reformed to the solid-supported heterogeneous catalytic systems by Zhao’s group and Cai’s group, respectively [14,15]. However, these strategies rely on the use of transition-metal catalyst and carcinogenic solvent DCB. Alternatively, N-(2-pyridyl)amidines could be converted into 1,2,4-triazolo[1,5-a]pyridines in the presence of stoichiometric amounts of external oxidants, such as phenyliodine(Ⅲ)bis(trifluoroacetate) PIFA [16], I₂ [17], isocyanuric chloride [18], in organic solvent (Scheme 1b). In 2019, Zhang’s group disclosed an electrochemical protocol to deliver the scaffold with ⁿBu₄NBr as the redox mediator in CH₃CN (Scheme 1c) [19]. The use of organic solvent will bring the cost increasing, environmental threat, toxicity issues, and safety hazard. While, water is a low cost, environmentally benign, nontoxic, and non-flammable alternative. Therefore, developing the reactions conducted in water represent a vibrant area of investigation both in industry and academia [20-47].

Scheme 1

Scheme 1. The synthesis of 1,2,4-triazolo[1,5-a]pyridines in water.

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The amino diphenylphosphinate (DPPH) as amino source was successfully applied in various nitrogen insertion reactions [48-52]. However, aminations using DPPH conducted in water are rarely reported, and construction of the hetero-aromatic ring with DPPH is underdeveloped. With our continued interest in developing sustainable strategy to the construction and derivatization of privileged scaffolds [53-60], we herein report an additive-free procedure to access 1,2,4-triazolo[1,5-a]pyridines from the readily available N-(pyridyl)amides and amino diphenylphosphinate in water (Scheme 1d).

We carried out the study with N-(pyridin-2-yl)benzamide (1a) and amino diphenylphosphinate (2) as the substrates. The first model reaction was conducted in DMF at 100 ℃ under N₂ atmosphere, affording the desired product 3a in 74% yield (Table 1, entry 1). Firstly, the effects of the base were investigated (entries 2–6). The use of Et₃N, K₂CO₃, NaH, NaOH, or KOH retarded the reaction. Green solvents H₂O, polyethyleneglycol (PEG400), ethylene glycol (EG), cyclopentyl methyl ether (CPME), 2-MeTHF, or dimethyl carbonate (DMC) were then evaluated (entries 7–12). It was found that H₂O (87%, entry 7) outperformed other green solvents (63%−82%, entries 8–12) in terms of the yield. Changing the reaction atmosphere from N₂ to air or O₂ has no adverse effect on the reaction efficiency (entries 13 and 14), indicating that the transformation is insensitive to O₂. Thus, the optimized conditions were identified as follows: 1a (0.2 mmol), 2 (2 equiv.), H₂O (3 mL) as a solvent, at 100 ℃ under N₂ atmosphere.

Table 1

Table 1. Optimization of reaction conditions.^a

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With the optimal cyclization conditions at hand, the scope of the reaction was firstly investigated by variation of the R¹ group in N-(pyridyl)amide 1a (Scheme 2). The result indicated that a variety of substitutions on the aromatic moiety were well tolerated regardless of their electronic properties or steric properties. For example, both electron-donating (Me, Et, OMe) and electron-withdrawing (F, Cl, Br) substitutions on para-, meta-, or ortho-positions of the phenyl group were well compatible, affording the desired products 3b-3k in 51%−98% yields. Moreover, the N-(pyridyl)amides 1l and 1m bearing the valuable pharmacophores (acetyl and phenoxy group) reacted smoothly to give the desired products 3l and 3m. Unfortunately, N-(pyridyl)amide with nitro substitution was not compatible to the standard conditions. With R¹ being heteroaromatic rings (1n-1o), the reactions uneventfully afforded the corresponding products 3n-3o in 51% and 40% yields. Importantly, the substrates 1p-1t, with R¹ being an alkyl, also turned out competent, retrieving the cyclized products 3p-3t in 19%−74% yields. Moreover, the structure of product 3a was confirmed by the X-ray single crystal diffraction studies.

Scheme 2

Scheme 2. Scope of the phenyl ring in N-(pyridyl)amide. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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We next turned our attention to study the effects of substitutions on the pyridine moiety (Scheme 3). Electron-donating groups on the different position of pyridine ring, such as 4-Me, 4-Et, 4-MeO-, 5-Me, 6-Me, 3-Me, and 3-MeO were amenable to the standard protocols, giving the desired products 3u-3aa in 48%−96% yields. Furthermore, the substrates 1ab-1ag with electron-withdrawing substituents (4-F, 4-Cl, 4-Br, 4-pH, 4-CF₃, 5-Br) also proceeded smoothly and afforded the anticipated products 3ab-3ag in moderate to good yields. To our delight, the products 3ah-3aj were also delivered in 60%−93% yields when there were substituents both on the pyridine ring and aryl ring.

Scheme 3

Scheme 3. Scope of the pyridine ring in N-(pyridyl)amide. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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To highlight the usefulness of this sustainable strategy in medicinal chemistry, we conducted the late-stage modification of valuable natural products and pharmaceuticals (Scheme 4). The N-(pyridyl)amides derived from levulinic acid (1ak) and elaidic acid (1al) reacted efficiently to produce the products 3ak-3al in 34% and 62% yields, respectively. Furthermore, the method could also be successfully applied in the functionalization of nonsteroidal anti-inflammatory drug (lbuprofen, 1am), lipid regulators (gemfibrozil, 1an), and cholagogues (dehydrocholic acid, 1ao). The value of these current methods was further displayed by a scale-up synthesis which afforded the desired product in 70% yield (see Supporting information for details).

Scheme 4

Scheme 4. The late-stage modification of natural products and drugs. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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Considering that amino diphenylphosphinate is a typical electrophilic amination reagent widely used in the regioselectivity N—N coupling reaction [61-65], a plausible mechanism for the amination/cyclization reaction is depicted in Scheme 5. Initially, the pyridine in 1 attacks amino diphenylphosphinate 2, generating the N-aminopyridinium phospate salt 4, which exists in three resonance forms 4a-4c. The amino group attacks the carbonyl group intramolecularly to afford diphenylphosphinic acid 5 (detected by HRMS) and 6. Then, intermediate 6 underwent dehydration with the aid of acid 5 to give the final product 3 [66,67].

Scheme 5

Scheme 5. The proposed mechanism.

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In summary, we have developed a green and high yielding strategy for the amination/cyclization of N-(pyridyl)amides to access the 1,2,4-triazolo[1,5-a]pyridines in water. The transition metal- and oxidant-free protocol demonstrates broad substrate scope and exceptional functional group tolerance. The utility of this protocol is also highlighted in late-stage modification of several natural products and drugs. Accordingly, we anticipate that this sustainable protocol will be of great utility to the pharmaceutical chemistry as well as many other fields.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We acknowledge the financial support from the National Natural Science Foundation of China (No. 82003585), the Program for Science & Technology Innovation Talents in Universities of Henan Province (No. 24HASTIT069), the Technical Innovation Team of Henan Normal University (No. 2022TD03), the Special Project for Fundamental Research in University of Henan Province (No. 23ZX009), the Henan Science and Technology Program (No. 232102310364), the Key Project of Henan Educational Committee (No. 22A150041), Excellent Youth Foundation of Henan Scientific Committee (No. 222300420012), the Young Core Instructor Training Program of Xinyang Agriculture and Forestry University (2023).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.109755.
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Figure 1 The bioactive molecules bearing the 1,2,4-trizaolo[1,5-α]pyridines fragment.

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Scheme 1 The synthesis of 1,2,4-triazolo[1,5-a]pyridines in water.

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Scheme 2 Scope of the phenyl ring in N-(pyridyl)amide. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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Scheme 3 Scope of the pyridine ring in N-(pyridyl)amide. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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Scheme 4 The late-stage modification of natural products and drugs. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv.), H₂O (3 mL), 100 ℃, 10 h, N₂. Isolated yields were given.

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Scheme 5 The proposed mechanism.

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Table 1. Optimization of reaction conditions.^a

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